Phenyltropane

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Phenyltropane
Except where noted otherwise, data are given for
materials in their standard state
(at 25 °C, 100 kPa)
Infobox disclaimer and references

Phenyltropanes (PT) are a bunch of semi–synthetic azabicyclic tropane alkaloids structurally derived from ecgonine.

Contents

[edit] Sites of Action of Cocaine

[edit] N-Adrenaline Related[1]

The dopamine (DA) efflux in the medial prefrontal cortex (mPFC) can be modulated by the interaction between afferent norepinephrine (NE) and somatodendritic DA in the ventral tegmental area (VTA). However, it is unclear how locally administered amphetamine (AMPH) or cocaine in the VTA results in discrepant response of DA efflux in the mPFC. In this study, intra-VTA infusion of AMPH (1000 microM) or cocaine (200 microM) in anesthetized rats was employed to study the concurrent profile of extracellular DA level in the VTA and mPFC. In addition, the extracellular NE levels during the intra-VTA infusion of these two psychostimulants were analyzed to compare their effects on prefrontal DA efflux. During the intra-VTA infusion of AMPH, both extracellular DA and NE increased significantly in the VTA (270 +/- 12% and 819 +/- 40%, respectively). Meanwhile, the DA efflux in the mPFC elevated significantly. During the intra-VTA infusion of cocaine, the extracellular DA and NE in the VTA also increased (271 +/- 21% and 150 +/- 15%, respectively). However, the DA efflux decreased significantly in the mPFC. Noteworthy, the increase of extracellular NE in the VTA was much more robust via AMPH infusion, as compared with cocaine. It is suggested that AMPH and cocaine enhance the extracellular NE concentrations in the VTA in different magnitudes, which in turn contribute to discrepant profiles of distal DA efflux in the mPFC.[2]

Nortropanes are much more NET selective than the Me-N compounds from which they are derived. Transfixing azabicyclic tropane diastereoselectivity from 2β,3β– to 2β,3α– conformation indents a downward shift in the molecules spatial outlay, from the common 'chair' to a flattened-boat, in attempt to reduce steric strain. p-Me,F,Cl (2β,3α)-N-PT's are relatively MAT nonselective with IC50s ranging from 5-9nM (NET), to 3-34nM (DAT), to 53–500nM (SERT). The (p-Me, m-F) disubstituted N-PT has the sharpest NET affinity/selectivity and is 21-fold selective vs. 5-HTT and 55-fold vs. DAT. This NET selective tool may prove useful in probing NET importance w.r.t. psychostimulant abuse. Please visit my Nocaine page, as this was recently done for radioactive Nocaine/modafil hybrids. Please see my SNDRI page for associated DPRK work
Clonidine (NA α-2 blocker) attenuated acute responding to cocaine on day 1 and retarded increased LMA on the next 2 days. Cocaine sensitization was dramatically increased even after the 1st challenge. However, cocaine sensitization expression was inhibited during the reinstatement protocol. These results imply α-adrenoreceptors are important in modulating different stages of cocaine sensitization and probably cocaine addiction.[3]

To further explore the structure–activity relationships of conformationally constrained tropanes, a number of new biaryl and arylacetylene analogs were designed and synthesized. Some of these compounds such as 3a–b, 3d, 3f–h, 5b, and 7g were found to be highly potent and selective or mixed norepinephrine transporter (NET) inhibitors with Ki values of 0.8–9.4 nM. Moreover, all of these compounds display weak to extremely weak muscarinic receptor binding affinity, indicating that as potential antidepressants, they may overcome certain side effects that are of concern with other antidepressants, which are thought to be mediated by their anticholinergic properties.

. Effects of cocaine on release of noradrenaline (NA) from sympathetic nerves were studied in the isolated perfused central artery of the rabbit ear. Indices of release were the vasoconstrictor response to nerve stimulation and stimulation-induced overflow of radioactivity after the nerves had been loaded with [3H]-NA. The overflow studies were carried out on phenoxybenzamine-treated arteries to eliminate the effect of cocaine on neuronal uptake. 2. Cocaine enhanced the constrictor responses of the artery to stimulation in concentrations of 3 and 30 mumols/l, but in higher concentrations (tested up to 300 mumols/l) the enhancement declined and was replaced by inhibition. Responses to extraluminal NA remained enhanced throughout the concentration range (tested up to 150 mumols/l). 3. In contrast, cocaine depressed the overflow of radioactivity, the effect being detectable in a concentration of 3 mumols/l (a decrease of 15%); the decrease was 40% at the highest concentration tested (90 mumols/l). 4. It is suggested that when assessed in terms of the vasoconstrictor response, inhibition of transmitter release by cocaine is masked by inhibition of neuronal uptake except in high concentrations of cocaine.

[edit] 5-HT Related

5-HT agonists lacking dopaminergic activity have been found not to produce reward or euphoria. However, intelligence suggests 5-HTT inhibition modulates cocaines reinforcing properties.[4][5][6][7][8] If 5-HT synapses on the cell body of DA neurons regulate reward threshold levels, then cocaine inhibition of 5-HT uptake could enhance or reduce cocaine-induced effects in the dopaminergic system. Even though the importance of the 5-HTT in mediating the neurochemical & behavioral actions of cocaine is now recognized, the biochemical mechanism of action and regulation of this transporter is not well understood. This has led to the design and synthesis of cocaine analogs which would bind selectively to the 5-HTT site. 5HT based-agents are being investigated as possible medications for the treatment of cocaine abuse as well.[9] Interestingly, 5HT inhibitors lacking dopaminergic activity do not produce reward or euphoria.
[10][11][12]

However, evidence also suggests that SERT inhibition might have a modulatory role in the reinfocing properties of this drug.[13]

There is still much conflict though, whether 5-HT is a good or a bad thing as far as +ve reinforcement is concerned. Predosing non-human primates with high doses of an SSRI and a direct 5HT agonist attenuated cocaine SA relative to saline controls.[14] In vivo microdialysis studies revealed that this was consistent with the serotonergic drugs inhibiting the release of DA in vivo.

[edit] DA Related

Cocaine is an equipotent inhibitor of neuronal DA, SER & NE transporters.[15][16] However, inhibition of the DAT appears to be critical to the behavioral stimulant and reinforcing effects of cocaine associated with its significant abuse.[17] It is common knowledge that cocaine inhibits the re/uptake of dopamine into presynaptic vesicles. There is a strong link between the reinforcing effect of this drug, and stimulants in general, with elevated DA levels in the nucleus accumbens.[18][19][20][21][22][23][24][25][26] In addition to this there is evidence that cocaine anticipation can also elevate DA levels, in the dorsal striatum and the caudate nucleus too.[27][28] Interstingly antipsychotic compounds such as Olanzapine can serve to decrease cocaine self-administration.[29] Even though it is not reliably self-administered, olanzapine increased DA to ~190% controls. Lastly pretreatment with fluoxetine had no systematic effect on olanzapine-induced increases in striatal DA. Recent advances in NI techniques involving PET[30] and radiotracer ligands show that the level of occupancy of cocaine at the DAT correlates well with the time–scale of the subjective ‘high’ reported by cocaine users. Further evidence is provided by tests on non-human primates which have shown that IV cocaine rapidly elevates extracellular DA which can be monitored in vivo with microdialysis probes.[31] >70% DAT occupancy is required inorder to induce euphoria, ≈40% merely serves to maintain addicts in the treatment program.[32]

[edit] σ–Receptors

[edit] Other

It is not known whether the binding sites for cocaine are unique and whether this accounts for the exceptional abuse potential of cocaine among all compounds that block DA uptake. It is known to have multiple effects on the CNS, including potent S/N/D/RI and also interaction with cholinergic, σ–receptors and Na+ channels.[33] Over the last several years, substantial animal data has accumulated to support this hypothesis.HP Natürlich (2R,3S) cocaine has appreciable DAT affinity, but the 7 remaining man-made isomers were 60-600 fold weaker.[34] The short half-life of cocaine is attributed to the fact that both of its ester groups are quite easily hydrolyzed to inactive compounds.[citation needed] Molecules containing the ester functional group don’t necessarily always degrade rapidly, and there are clear–cut exceptions to this over-simplification, including many anticholinergic compounds. However, in the case of cocaine the onset time is rapid and the effects are short lasting. The speed of onset hypothesis has received hefty support in accounting for cocaines solid abuse potential.[35]

[edit] Introduction

The 3-phenyltropane classes of MARI’s are both more potent in vitro and in vivo and more metabolically stable than cocaine. In addition, they have a slower onset of action and much longer duration of action. WIN-35,065-2 displays a much higher DAT selectivity than cocaine in vitro and is also more potent in vivo. Phenyltropanes are not normally local anesthetics because they lack the required ester link adjoining the tropane and phenyl rings. The most commonly used simple phenyltropane analogues in research are β-CFT, RTI-55 (β-CIT), and the Nor-p,m-Cl2 analogue Dichloropane. WIN-35065-2 (β-CPT) is also available; it is as potent as cocaine, although longer lasting due to increased metabolic stability. The MeO- from the 2β-CO2Me group can also be replaced to yield compounds with superior DAT affinity, that are even more metabolically stable, with the most potent analogues of β-CIT and dichloropane for instance being the carboisopropoxy and pyrrolidinylcarboxamide derivatives. The 2β-CONMe2 ester of β-CIT is a particularly promising target. Substitution on the nitrogen can also be successful in some instances, with the N-(γ-fluoropropyl) analogue of 2-carboisopropoxy-β-CIT being more potent than the simple N-methyl derivative.

[edit] DA Autoreceptors

Release and uptake are primary components of DA neurotransmission. The release of DA into the synaptic cleft and its subsequent diffusion to target cells initiates signalling, which is terminated by a transporter clearing of the neurotransmitter from extracellular space. The efficacy of release-regulating autoreceptors is clearly demonstrated in vitro by potent D2 inhibition of DA levels elicited by a single electrical pulse[36][37] and rapid (<100msec) response after receptor activation.[38][39] Autoreceptors provide important feedback control during DA signalling by governing firing rate, synthesis and release.[40][41] More recent identification of uptake-regulating auto-receptors[42][43][44][45] [46][47] suggests complex presynaptic control of DA neurotransmission. Indeed, autoreceptors may contribute to regional variation in extrasynaptic communication determined by differential DAT activity.[48][49][50] DAT gene deletion also reveals an intimate association among transporter, autoreceptor, and terminal homeostasis.[51][52] Extracellular DA dynamics elicited by pulse train stimulation reflect the blanace between the opposing actions of release and uptake. Because individual components are resolved by real-time voltammetry and mathematical means[53] these evoked signals are ideally suited for investigating autoreceptor interactions. Interstingingly, only release-regulating autoreceptors have been identified using this approach in vivo.[54] Whether this result reveals properties of integrative autoreceptor control of DA transmission in the intact brain or experimental limitations requires additional investigation.

The DAT in neuronal plasma membranes clears DA from the (extra)synaptic space[55] by an active uptake process with cotransport of Na+/Cl- but probably not countertransport of K+; the latter is similar to the case for NET but unlike SERT. Thus DA uptake depends on the presence of Na+/Cl- with K+ being primarily inhibtory.[56] DA uptake is a complicated electrogenic process composed of different steps such as external ligand recognition, translocation, internal ligand release, and reorientation of the carrier to the conformation with the recognition site facing externally.

[edit] Rodent Behaviour

Genetically modified, DAT knock-out rats have elevated DA levels that accumulate in the synaptic cleft and consequently, display symptoms of overt hyperactivity etc.[57][58] The laboratory rat test-subjects still self-administered cocaine though; this prompted scientists into assuming cocaine-induced SERT inhibition partially mitigates rewarding effects.[59] For some reason, the included reference makes the wild claim that NET inhibition only causes aversive effects, this might be erroneous though - i'll cross validate it.--Nuklear 10:18, 5 April 2007 (UTC) Recent technological advancments created DAT knock-in mice where the DAT is still fully functional, with the important exception that the cocaine recognition site was genetically modified so that DA re/uptake cant be blocked simply by consuming cocaine.[60] DAT KI mice do NOT self-administer cocaine. This recent study was very effective in undermining spin-out hypotheses and has revalidated the general tenets laid down by the DA hypothesis.

[edit] Monkey Coke[61][62]

A pair of local anesthetics were compared with cocaine for their ability to occupy DAT and elicit associated enhancements in extracellular DA. It was shown that local anesthetics can cause behavioral stimulation similar to cocaine, but one must realize that this property is distinguishable from the Na+ channel blocking effex which cause local anesthesia. Hence local anesthetics are not automatically euphoriants, whereas compounds that have a high level of in vivo DAT occupancy at the ED50 tend to function as +ve reinforcers. Hence, procaine does not function as a +ve reinforcer whereas dimethocaine can be abused even though it’s DAT vs. Na+ blocking potency ratio is 10-fold inferior to cocaine. It is pertinent to point-out that Na+ blockers can be quite cardiotoxic in overdose scenarios, and so abusing high doses of local anaesthetics for their stimulant side effects is likely to be more dangerous than taking cocaine itself.

[edit] p-Substituted Phenyltropanes

Cmpd. p-atom DAT IC50nM NET IC50nM SERT IC50nM
Cocaine Cocaine 102 3298 1045
WIN 35,065-2 H 23.0 920 1962
WIN 35,428 F 22.9 38.6 100
RTI-31 Cl 1.12 37 44.5
RTI-51 Br 1.7 10.6 37.4
RTI-55 I 1.26 36 4.21
RTI-32 Me 1.7 60 240

Enhancements in potency can be achieved via p-substitution into the phenyl nucleus. DAT activity "peaks" for p-Cl phenyl in the case of mono-substitution, but any substituent yields superior activity to the bare phenyl-ring. Nonselective RIs is the general result of p-substitution, although this position is most consistent with DARI, at least in the case of smaller substituents. Although as the size of the p-substituent increases, SERT inhibition also becomes apparent. The p-CH3 group is not very successful at turning-on the discriminative stimulus, even though its in vitro DAT occupancy = RTI-51. E.g. in a rat CD study, RTI-31 and RTI-32 were found to be 26.8 and 6 x more potent than cocaine.[63] It is considered roughly on the same order with a p-fluoro atom in terms of actual in vivo potency, but other considerations include efficacy as a reinforcer, not sheer potency. For instance, cocaine is not a very potent DAT inhibitor, and yet it is arguably the most powerful +ve reinforcer known. Although it must be stressed, that there are those who prefer their amphetamines. Even though the potency in behavioral studies does not exactly parallel the DAT binding and uptake inhibition data, there is a rank order correlation. Thus the more potent compounds in behavioral studies tend to be more potent in DAT binding. Alternatively m-substitution yields compounds with greatly strengthened SERT potency relative DAT.[citation needed] These however, are not thought to be +vely reinforcing and will not be discussed further, other than in the context of my tropadol idea.

[edit] Diastereoisomers[64]

Clarke et al. originally set out to separate the stimulant actions of cocaine from its toxicity and dependence liability.[65][66] Most PT research has focused on the 2β,3β–diastereoisomers because it is common knowledge that these possess higher activity than the weaker 2α,3β–diastereoisomers.[67][68][69] It was also of interest to look at other variations of simple p-substituted analogs alongside the β,β-conformation, in an attempt to acertain a deeper level of understanding on what structural features are necessary for activating the MAT receptors, and in how much flexibility there is with what can be successfully tolerated. Particularly so, since brasofensine and tesofensine both possess trans-diastereochemistry. The other diastereoisomers of PT are the 2α,3β– and 2β,3α-isomers, although the latter is not immediately derived from alkylecgonidine and employs an unnatural-synthetic pathway.[70] The α,α-isomers are completely worthless & has been pruned for clarity. The MAT binding properties, gross behaviour (GB), LMA effects in a mice and CD results in cocaine-trained rats of a variety of PT isomer variations are reported. Notice that (2) was deliberately drawn in a twist-boat conformation.

[edit] MAT Affinity & Gross Behaviour

Steroisomers
Cmpd. p-atom DAT IC50nM NET IC50nM SERT IC50nM 1 mg/kg 10 mg/kg 100 mg/kg
Cocaine Cocaine 89.1 3300 1050 HA C,Sy,HA
1a H 23 920 1960 Sy,HA Sy,HA,Cc C,Sy,ST
1b F 13.9 835 692 Sy(sl),HA(sl) Sy,HA C,Sy,ST
1c Cl 1.1 37 44.5 Sy,HA,Cc Sy Sy,HL,ST
1d Br 1.7 37.4 10.6 Sy,HA Sy,Cc Sy,Cc
1e I 1.3 36 4.21 Sy,HA,Cc Sy,HA(sl),Cc D,Sy,HA(sl),HL
1f Me 1.7 60 240 Sy Sy
2a H 101 541 5700 Sy,HA(sl) Sy,HA,Cc
2b F 21.0 1200 5060 Sy,HA(sl),Cc Sy,HA,Cc
2c Cl 3.1 5.14 53 HA Sy,Cc,Sn
2d Br 1.7 32.4 84 Sn Sy,HA Sy,Cc
2e I 2.9 52.4 64.9 HA(sl)
2f Me 10.2 270 4250 HA(sl) Sy,HA,Cc
3a H 670 >10000 >10000 C,Cc,Sn,HL,T,A
3b F 325 7200 >10000 Sy(sl) C,Sy,Ho,Cc,T
3c Cl 25.0 444 1450 Sn D,C,Sy,Cc,T,A,ST
3d Br 15.7 272 570 Sy,Ho,P D,C,Sy,Ho,Cc,P,ST
3e I 22.7 760 66.3 Sy(sl) D,C,Sy,HL,T,ST
3f Me 207 2230 >10000 Sn(sl) C,Ho,Cc,HL,A
A, ataxia; C, convulsions; Cc, circling; D, death; EG, excessive grooming; FBP, flattened body posture; HA, hyperactivity; HL, hind limb splay; Ho, hypoactivity; MR, muscle relaxation; P, ptosis; (sl), slight or intermittent; Sn, stimulation; T, Straub tail; Sy, sterotypy; T, tremor.
  • All of the compounds have DAT affinity exceeding SERT/NET affinity.
  • Isomer: 2β,3β; order of DAT IC50: p-Cl ≈ p-I ≈ p-Br = p-Me > p-F > p-H.
  • Isomer: 2β,3α; order of DAT IC50: p-Br > p-I ≈ p-Cl > p-Me > p-F > p-H.
  • Isomer: 2α,3β; order of DAT IC50: p-Br > p-I > p-Cl > p-Me > p-F > p-H.
  • DAT affinity of the 2β,3β-isomers > 2β,3α-isomers >> 2α,3β-isomers.
  • The 2α,3β isomers are particularly poor, and the p-H,-F,-Me compounds have DAT affinity that is even weaker than cocaine.
  • It is particularly important to recognize that (2α,3β)p-Cl,Br,I isomers produced death at 100 mg/kg.
    • In contrast, none of the 2β,3α-isomers and only the p-I isomer 1e produced death at 100 mg/kg (although the ED50 is quite low here)..
  • With the exception of 1e, the general pattern is the weaker PT isomers appear to yield more harmful outcomes at higher doses.

[edit] Locomotor Activity (LMA)

LMA studies were reported previously for RTI-51 & RTI-55, where both compounds were shown to behave as similarly powerful psychostimulants in mice.[71][72] In the current study, RTI-55 was shown to function as an absurd LMA stimulant.

Maximized & Normalized LMA in Mice (ip) over 4 h for compounds 1a-f
Cmpd. dose mg/kg hour 1 hour 2 hour 3 hour 4 dose mg/kg hour 1 hour 2 hour 3 hour 4 ED50 in peak hour
cocaine 30 +341 +100 -10 +16 10 +127 +24 +10 -21 10
1a 10 +904 +1080 +964 +190 1 +253 +192 +102 +151 1.2
1b 3 +633 +558 +199 +140 1 +333 +232 +28 -29 0.7
1c 1 +645 +958 +1892 +1507 0.3 +462 +1426 +1201 +235 0.2
1d 1 +258 +35 +302 +656 0.3 +259 +598 +869 +834 0.1
1e 1 +1489 +1721 +2099 +2546 0.3 +415 +1765 +1289 +900 0.4
1f 3 +533 +460 +157 +30 1 +305 +298 +41 -4 0.6

Locomotor Activity in Mice (ip) over 4 h for compounds 2a-f & 3a-f

Cmpd. dose hour 1 hour 2 hour 3 hour 4 ED50 in peak hour Cmpd. dose hour 1 hour 2 hour 3 hour 4 ED50 in peak hour
2a 10 +43 +6 -13 +6 21.8 3a 30 +138 +122 +69 +12 7.7
2b 30 +362 +187 +215 +66 15.6 3b 10 +58 +107 +260 +196 2.4
2c 10 +340 +322 +373 +11 9.1 3c 10 +248 +1003 +1275 +667 4.3
2d 3 +60 +88 +100 +109 6.6 3d 10 +49 +268 +267 +74 10
2e 10 +210 +100 +457 +49 7.7 3e 30 +7 +150 +268 +255 10
2f 30 +482 +147 +5 -66 14.7 3f 30 -23 +7 +17 +42 Fail

[edit] Cocaine Discrimination (CD) Studies

For other CD studies see attached link.[73]

percent of rats choosing the cocaine lever at the dose (mg/kg) specified

Cmpd. 0.1 0.17 0.3 0.56 1 1.7 3 5.6 10 17 30 ED50, mg/kg
Cocaine 21 32 59 82 97 2.44
1a 14 36 88 100 0.34
1b 0 57 86 100 0.29
1c 50 44 100 0.13
1d 14 50 100 0.17
1e 22 25 100 0.20
1f 0 25 57 71 86 0.31
2a 13 100 100 3.19
2b 29 38 86 5.66
2c 25 25 67 67 100 2.55
2d 13 13 50 88 2.98
2e 0 14 43 44 86 5.66
2f 0 14 29 43 43 75 100 7.73
3a 29 67 100 7.66
3b 0 33 57 100 8.01
3c 13 88 67 4.01
3d 25 17 86 7.29
3e 0 14 80 13.51
3f 13 43 71 71 100 13.51

Thus, the higher MAT binding affinity, greater potency and duration of action assays, as well as the lower toxicity as judged by observed gross effects, suggest that the 2β,3β / 2β,3α–isomers are more likely to be candidates for pharmacotherapies to treat addiction and other CNS disorders, than the 2α,3β–isomers.

This study shows that RTI-31 is likely to be a good stimulant whereas the WIN compounds are weaker and less likely to be of value from an economic standpoint.

[edit] RTI Library Compounds

[edit] RTI-76[74]

RTI-31-p-isothiocyanato-phenylmethyl ester is an irreversible inhibitor of the DA transporter. RTI-76 effectively removed the uptake component from recorded signals. Recent evidence suggests that release and uptake, key mechanisms determining brain extracellular levels of DA, are governed by presynaptic autoreceptors. The goal of this study was to investigate whether autoreceptors regulate both mechanisms concurrently. Extracellular DA in the caudate-putamen and nucleus accumbens, evoked by electrical stimulation of the medial forebrain bundle, was monitored in the anesthetized rat by real-time voltammetry.

[edit] RTI-336[75][76][77]

RTI-336 showed LMA less than cocaine with no sensitization. It was orally active in both LMA tests on mice and CD tests in rats and had an excellent TR. RTI-336 reduced cocaine self-administration in both rat and rhesus monkey models and showed slow onset and long duration of action in rodent and monkey models. These preliminary studies in rhesus monkeys showed that RTI-336 was effective in suppressing cocaine self-administration at doses that had no obvious adverse behavioral effects. Varying the maintenance dose of cocaine had no influence on the effectiveness of drug pretreatments. There was no evidence of selective reductions in cocaine self-administration compared with food-maintained behavior. High levels of DAT occupancy were required to produce robust reduction in cocaine use. RTI-177 is the compound lacking the p-methyl.
In a separate study, pretreatment with RTI-336 was characterized in rhesus monkeys trained to self-administer cocaine under a schedule of i.v. drug or food delivery. In addition, RTI-336 was substituted for cocaine to characterize its reinforcing effects. Last, the dose of RTI-336 that reduced cocaine-maintained behavior by 50% was coadministered with the SSRIs fluoxetine and citalopram to characterize their combined effects on cocaine self-administration. PET neuroimaging with the SDARI radioligand Nor-18FCT quantified DAT occupancy at behaviorally relevant doses. RTI-336 pretreatments produced dose-related reductions in cocaine self-administration, and the ED50 dose resulted in approximately 90% DAT occupancy. RTI-336 was reliably self-administered, but responding was lower than that maintained by cocaine. Doses of RTI-336 that maintained peak rates of responding resulted in approximately 62% DAT occupancy. Coadministration of the ED50 dose of RTI-336 in combination with either SERT inhibitor completely suppressed cocaine self-administration without affecting DAT occupancy. Hence, at comparable levels of DAT occupancy, coadministration of SERT inhibitors with RTI-336 produced more robust reductions in cocaine self-administration than RTI-336 alone. Collectively, the results indicate that combined inhibition of DAT and SERT warrants consideration as a viable approach in the development of cocaine medications.

[edit] RTI-51[78]

RTI-51 appears to have favourable ADME characteristics that make it a promising candidate to act as a potential legal substitute drug for human consumption, as an alternative to cocaine or similar illegal drugs.

[edit] RTI-113[79][80]

RTI-113 is a SDARI with a rapid onset and long duration of action. Like cocaine it is a behavioral stimulant and robust reinforcer. Although its DAT occupancy is almost 100% vs. cocaine ~70%, rates of SA in non-human primates was actually less. It is hypothesized that this might be a pharmacodynamic effect in that repeat doses would be likely to accumulate over a session making sustained self administration less likely than cocaine. Importantly predosing with RTI-113 attenuated cocaine SA. This is not necessarily a generalized effect of extracellular DA either since WIN-35,428 and d-amphetamine do not affect cocaine response rates. It has been suggested that drugs eliciting limited amounts of reinforcing behavioral effects may be beneficial from the view-point of maintaining addicts in treatment programs thereby decreasing the likelihood of illicit drug use. However drugs which function as powerful behavioral stimulants and robust reinforcers may not be desirable where long term abstinence is the goal. [Also note that the –CO2Ph is less suceptible to hydrolysis than –CO2Me on a purely steric argument, but you also have to factor in that phenol is slightly/weakly acidic].

[edit] RTI-112[81]

RTI-112 has in vitro SNDRI selectivity similar to cocaine. Although the compound attenuated cocaine SA in non-human primates, it is not a robust behavioral stimulant and produces response rates that arent >>saline. PET scans reveal DAT occupancy was below the level of detection at the ED50 for RTI-112 whereas the SERT was almost saturated at this dose. However upon high doses of RTI-112 DAT occupancy became apparent. This finding shows that although DAT occupancy is strongly linked to the euphoriant effects of stimulant drugs, SERT inhibition might attenuate the propensity for cocaine to raise extracellular DA.

  • This result lends support to the notion that in vivo analysis can supply data that is not made apparant from a set of in vitro IC50 values.
  • In another study, RTI-112 was shown to be more potent than bupropion as a noncompetitive nicotinic antagonist.[82]

[edit] 3D QSAR CoMFA[83][84][85]

[edit] Ester Modification

[edit] 2β-Ester-3β-phenyltropanes

In these phenyltropanes the methyl group of the 2β-ester function is replaced with other alkyl, aryl, or alkylaryl groups. A large number of compounds have been made. Among 3β-4'-chlorophenyls, only 2β-isopropyl ester was slightly more potent than the parent compound. Other esters were less potent.
The interesting finding from this series of compounds was that the i-propyl ester and phenyl ester analogs possessed high selectivity for the DAT. It is also important to note that bulky ester groups are well tolerated without any significant loss in potency.[86]

R group p-atom DAT IC50nM NET IC50nM SERT IC50nM R group p-atom DAT IC50nM NET IC50nM SERT IC50nM
i-propyl H 85.1 32047 23121 p-tolyl Me 81.2 4096 15984
i-propyl Cl 1.4 778 1400 c-butyl Me 3.74 4738 2019
i-propyl I 0.43 285 66.8 c-pentyl Me 17.8 2628 485
i-propyl Me 6.45 1926 6090 3-pentyl Me 19.1 3444 4499
phenyl H 76.7 19262 106149 p-chlorophenyl Cl 55 4883 16914
phenyl Cl 1.99 2960 2340 p-chlorophenyl Me 117 9519 42761
phenyl l 1.51 3791 184 p-I-phenyl Cl 32.6 968 1227
phenyl Me 3.27 5830 24500 p-MeO-C6H4- Cl 71 1522 19689
c-propyl Cl 0.96 235 168 p-MeO-C6H4- Me 95.6 3151 82316
c-propyl I 0.61 102 15.5 p-nitro-2-phenethyl Cl 2.71
c-propyl Me 1.68 644 1066 p-amino-2-phenethyl Cl 2.16
o-tolyl Cl 3.91 4783 3772 p-NH2-m-I-(2-phenethyl) Cl 2.51
o-tolyl Me 23.2 25695 11040 p-azido-m-I-(2-phenethyl) Cl 14.5
m-tolyl Cl 9.37 2744 2153 p-isocyanato-m-I-(2-phenethyl) Cl 5.3
m-tolyl Me 8.19 2136 5237 Uglyducky Cl 1.73

DAT selectivity can be further increased through replacing the –CO2R with other alkyl groups than methyl*. The i-propyl ester for example, also has slightly increased metabolic stability due to steric/electronic factors.[87] It is not a vast improvement though and shouldnt be regarded as such. This analogy doesnt apply to ritalin though, where even an ethyl ester is not well tolerated.[88]

[edit] Amides

  • In vivo demethanolization of the ester is still possible → dummy inhibitors. To obtain analogs with increased metabolic stability,
    –CO2Me → CO2H → C(O)Cl → –C(O)NR2.[89]
    • 3° amides were found to have higher DAT affinity than 1° and 2° amides.
    • RTI-31 –C(O)NMe2 amide has a DAT IC50 value of 1.28 nM and >>SER/NAR IC50 values is a potent super SDARI.
    • The –C(O)N(CH2)4 pyrrolidinocarboxamides are also similarly potent SDARI’s, although the –NEt2 amides are weaker.

Infact, it may be possible for us to react the ecgonidine-C(O)Cl with demethylamine directly. This type of reaction is very common in fentanyl synthesis. Please visit my Ohmefentanyl page to see the connection. Then if we do a standard organometallic addition we will get 100% 1,4-addition. Maybe the bromide can work here also??

An amide can undergo H-bonding, though weaker than an ester function deprending on its substitution pattern. The 2β-carboxamides, particularly with oxygen-bearing substituents were more potent within the same series of compounds. The most potent and the most selective analogs among carboxamides were RTI55-N-pyrrolidino carboxamide, and RTI31-N-morpholino carboxamide, respectively.

[edit] Heterocycles

  • The esters can also be functionalized into various heterocycles which are also more DAT selective and chem/metabol–ically stable than the crude esters. A whole slew of such compounds have been made and the literature is crammed with examples.

[edit] n-Propyl Group[90][91]

It appears in a recent patent that the i-propyl group also functions as a SDARI.

Pyrovalerone

Kozikowski reported some extremely powerful PT compounds in 1995 that had an n-propyl group. However the synthesis was not feasible. The new pyrovalerone compounds reported by Meltzer et al. can actually be commercialized although they are only Sched III and thus not thought to be highly abusable. The compound depicted has (S)-stereochemistry and should be baked as the enantiopure isomer where possible. It's a pure DAT inhibitor in its pharmacology and probably of low toxicity, and very cheap to manufacture. Even though it can competently function as a sDARI, IC50 values alone are probably not worth getting excited about, and even in the best case scenario it will only suppress illicit drug use and wont be strongly reinforcing, which is required, inorder to make killer sales... I still hypothesize that it is good from the standpoint of quitting smoking, since bupropion for example is rather weird. So it does have 'applications'. Since it possesses a β-keto FG, one could argue that it is vagualy related to cathinone, although this is of questionable validity.[92]

[edit] 2β-Phenyl Group[93][94]

This compound is similarly active to RTI-32 although the others were less impressive. It is likely to be long acting like desoxy-pipradol (pipradane).

1R,2S,3S Compound DAT IC50 (nM) NAT IC50 (nM) SERT IC50 (nM)
2β-phenyl-3β-phenyltropane 12.6 917 21,100
2β-phenyl-3β-(p-methyl)phenyltropane (RTI-422) 1.96 479 11,000

[edit] Strained 3°N Bridge-Head PT SARs[95][96][97]

The precise details of the binding interactions between these compounds and the MATs are still a matter of much discussion.[98] A pharmacophore model for the DAT based on conformational analysis of cocaine and TMP has been proposed.[99] Little is known experimentally about the spatial requirements of the nitrogen lone pair of these compounds. The directionality of the nitrogen lone pair is, however, likely to be of some consequence to binding affinity.[100]. image:tricycle.gif

Compound [3H]DA uptake [3H]NA uptake [3H]SER uptake
cocaine 425 83.3 155
(-)-1 60.3 5.24 1.76
(+)-1 114 4.26 1.48
(+-)1 60.3 2.69 2.32
6 24 1.77 1.06
3a 2.23 2.99 14
2a 10.2 15.0 78.9
3b 11.3 4.43 25.7
11a 149 51.7 810
10a 14.2 3.84 618

[edit] Nonselective p,m-Disubstituted PT Compounds[101]

A very common misconception with MATRIs is that the p,m-Cl2-phenyl ring pattern yields the most potent compounds. The results of this study clearly refute this. Early studies demonstrated that in vitro binding affinity was highly dependent on the nature of the substituents on the aromatic ring. For example, p,m-disubstituted analogues such as the p,m-Cl2 and (p-Cl,m-Me)-compounds were the first analogs reported to show <1nM affinity at the DAT.[102] Later reports showed that they also possess <1nM affinity at the 5-HTT.[103] Inhibiting 5-HT uptake may be an important characteristic of these compounds since a number of reports have suggested 5-HT indirectly modulates nucleus accumbens DA release.[104][105]

p-atom m-atom DAT IC50nM SERT IC50nM NET IC50nM
Cocaine Cocaine 89 1050 3300
H H 23 1060 920
Cl Cl 0.79 3.13 18
Cl CH3 0.82 10.5 36.2
Cl Br 0.42 0.78 7.24
Cl I 0.41 1.39 15.1
Br Cl 0.12 0.94 1.31
Br Br 0.27 0.71 2.80
Br I 0.21 1.14 10.4
I Cl 0.26 1.04 1.26
I Br 0.20 0.58 1.96
I I 0.98 2.0 40.4
CH3 CH3 0.43 9.88 107

RTI-112 has a high affinity for both the DA and 5HT transporters, and shows significant reduction in cocaine SA in rhesus monkeys, yet fails to maintain robust SA used alone. PET studies reveal that unlike SDAT analogs such as GBR 12909 and RTI-113, RTI-112 shows no detectible DAT occupancy when dosed at its ED50 for antagonizing cocaine SA. In contrast, it highly occupies the 5-HTT at this dose. The authors report the syntheses and MAT binding potency of several new 2β-CO2Me-3(p,m-disubstituted)phenyltropanes, which all have binding affinities very similar to RTI-112. With the exception of the p,m-Me2 analog, all of the compounds possess <1nM IC50 and Ki values at the DAT and 5-HTT, respectively. The (p-Br,m-Cl) analogue and the (p-I,m-Br) analogue are the most potent analogs at the DAT and 5-HTT. These compounds are particularly potent but might be less attractive as synthetic targets due to the considerably more complex synthetic routes required; it is very interesting to note the effect that p,m-disubstitution has on the observed potency, but the simple para-substituted compounds are sufficiently potent for practical purposes, and easier to produce.

[edit] Neurosearch Compounds

Neurosearch was founded by the inventor of Paxil (Christensen; Jorgen Anders (Virum, DK)).[106] paxilprogress.org Neurosearch has a strong focus on (1R,2R,3S)-diastereochemistry. In 1994 Neurosearch made the interesting claim that various trans-phenyltropanes also possess notable biochemical activity.[107] This has spawned some interesting molecules that have been tolerated to the point of being persued into the latter stages of clinical development. Trans-diastereochemistry seems better able to tolerate bulky substituents at the 2-position, than the cis-orientation, with regards to NAT/SERT affinity, judging by IC50 values. The only compounds currently receiving clinical evaluation from the 3-phenyltropane class are the 2α,3β compounds brasofensine[108] and tesofensine.[109][110] [Although Neurosearch is very secretive about its work so we cant be 100% sure about this].

These are potent (dose ~1–3mg) triple-mode reuptake inhibitors. [These are brand new, if you talk to your clinical practitioner about this, they wont know what the hell you are talking about because all the candidates are in the pipeline, and none of them are available in the public domain]. Neurosearch has been funded for this project by GlaxoSmithKline, however Boehringer Ingelheim has withdrawn funding because they failed to meet the predetermined criteria.

  • There is speculation that brasofensine can undergo trans/cis interconversion (tautomerization), which could potentially cause increased abuse potential as the cis-isomers of these compounds appear from animal studies to have greater reinforcing effects.
    I think this is just imine racemization (since there is restricted rotation about the unsaturated bond), not actually implicating piperidine diastereochemistry, as such. [Curr.Top.Med.Chem.2006].
(1R,2R,3S)-[p,m-C6H3Cl2]-Compounds DAT IC50 (nM) NAT IC50 (nM) SERT IC50 (nM)
2-[MeOCH2]-3-[p,m-C6H3Cl2]-tropane 10 2 10
2-(EtOCH2)-3-[p,m-C6H3Cl2]-tropane 8 3.2 11
2-[PhSCH2]-3-[p,m-C6H3Cl2]-tropane 4.3 2.8 9.2
2-[MeO-N=CH]-3-[p,m-C6H3Cl2]-tropane.sulfate 3 1.3 13
Nor-2-[MeO-N=CH]-3-[p,m-C6H3Cl2]tropane.HCl 2 1.3 1.7
2-[MeO-N=CH]-3-[p,m-C6H3Cl2]-tropane, syn-isomer 3.4 1.5 n.t
absol config [p,m-C6H3Cl2] Test Compounds In vivo ED50 (mg/kg) In vitro IC50 uM
(1R,2R,3S) 2-[MeO-N=CH]-3-(p,m-dichlorophenyl)-tropane-.H2SO4 0.90 0.0030
(1R,2R,3S) 2-[HO-N=CH2]-3-(p,m-dichlorophenyl)-tropane- 3.80 0.0034
(1R,2S,3S) 2-[HO-N=CH2]-3-(p,m-dichlorophenyl)-tropane 0.56 0.0020
(1R,2R,3S) Nor-2-[MeO-N=CH]-3-(p,m-dichlorophenyl)tropane.HCl 1.4 0.006
(1R,2S,3S) 2-[MeO-N=CH]-3-(p,m-dichlorophenyl)-tropane 0.37 0.0018

The following rating scale is used for the high intensity stereotypy on the condition that the behavioural syndromes are as described above:

+=only stereotyped sniffing ++=stereotyped sniffing and episodic licking +++=continuous licking and/or biting gnawing Compound (1R,2R,3S)-3-(p,m-Dichlorophenyl)tropane-O-methyl-aldoxime Dose(p.o.) Activity 15 mg/kg +++ is the lowest dosis giving the activity indicated.

This compound was also reported to be less potent than its 2β,3β-isomer but was chosen for development due to its better toxicological profile.

Brasofensine, which has the 2α,3β-stereochemistry, was reported to be less potent than its 2β,3β-isomer in both DAT in vitro and in vivo binding assays. Nevertheless, brasofensine is reported to show excellent efficacy, with a favorable adverse effect profile after oral administration in relevant animal models of Parkinson’s disease. In addition, a clinical study designed to investigate the safety of brasofensine in patients receiving levadopa/carbidopa treatment indicated that no serious adverse effects were experienced at doses of 0.5-4.0 mg/d.

  • Compounds Invented by Neurosearch,[113] currently recruiting obesity patients for clinical trials.

Mission: NeuroSearch is dedicated to the discovery and development of medicines to satisfy unmet medical needs. NeuroSearch’s core business focuses on diseases of the CNS primarily treated through modulation of ion channels and other membrane-bound transporters.

  • β,i-Naphthyl-propamines are proven anorectics, recently discovered by Rothman et al.[114][115]
    • This compound functioned as a monoamine releaser with comparible activity for all 3 of the common neurotransmitters.

serotonergics, the h5HT2c receptor is particularly notable.


[edit] Appendix

[edit] Reviews

Fundamental research with tropane-based ligands has generated a host of excellent reviews and issued researchers with many promising molecules.[116][117][118][119][120][121]

[edit] Applications of PT ligands

Addiction is a significant socioeconomic problem of our times. Evidence of cocaine addiction being a disease of the brain with specific neurobiological characteristics necessitates development of effective therapies to treat cocaine addiction.[122][123] <-Interestignly, this ref makes the wild claim that cocaine acts on the opioid receptors The dramatic advances in our understanding of the biological basis of drug abuse and dependence, together with advances in medicinal chemistry and neuropharmacology, support and motivate the search for pharmacotherapies effective as agents for pharmacological intervention.[124][125][126] Even though several pharmacological agents have been tried on the basis of various hypotheses, none of the pharmacotherapeutic approaches has proven effective.[127] Thus the incentive to provide effective pharmacotherapies in this area remains elusive. Numerous tropane-based ligands were synthesized for the purpose of selectively modulating DAT function and ultimately, with the goal of providing pharmacotherapies for various CNS diseases including depression, ADHD,[128][129] Parkinson's disease,[130][131] and addiction.[132][133]

[edit] p-Alkylated PT Analogs[134]

Increased lipophilic branching about the p-position hugely improves SERT binding affinity. Most compounds provided in the table, have SERT affinity that even surpasses DAT affinity.

  • Much more notable though is the effect that N-demethylation has on on SERT and NET affinity.
X N SERT IC50nM DAT IC50nM NET IC50nM X N SERT IC50nM DAT IC50nM NET IC50nM
Et Me 28.4 55 4030 Et H 8.13 49.9 122
n-Pr Me 70.4 68.5 3920 n-Pr H 26 212 532
i-Pr Me 191 597 75000 i-Pr H 15.1 310 ND
-C2H3 Me 9.5 1.24 78 -C2H3 H 2.25 1.73 14.9
i-propene Me 3.13 14.4 1330 i-propene H 0.6 23 144
t-CHCHMe Me 11.4 5.29 1590 t-CHCHMe H 1.3 28.6 54
c-CHCHMe Me 7.09 15 2800 c-CHCHMe H 1.15 31.6 147
CH2CHCH2 Me 28.4 32.8 2480 CH2CHCH2 H 6.2 56.5 89.7
C.CH Me 4.4 1.2 83.2 C.CH H 1.59 1.24 21.8
C.CMe Me 15.7 2.37 820 C.CMe H 3.16 6.11 116

[135][136]

[edit] PTrop-2-ene Analogs

One should also be aware of various benztropine analogs that are being researched exhaustively. β–NaphthylTropane

[edit] RTI PT Patent Search

Ivy Carroll Patents[137][138][139][140]

Most of the above compounds are created at RTI. 1 or 2 or the IC50 values in the CO2R section are a tad dodgy so i'll have to proof-read it, when I have time to.

Kuhar Patents[141][142][143][144][145][146]

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