User:Nuklear/Peridine

From Wikipedia, the free encyclopedia

Contents

[edit] Introduction

Pethidine is a weak μ-opioid that was introduced in the first half of the twentieth century. Meperidine is only moderately potent, requiring oral doses of ~100mg. Moreover, the parent compound is metabolized to N-demethyl meperidine which accumulates upon repeat administration and is toxic. Stacey Lomenzo, et al. introduced a number of substituted meperidine analogs just before the millenium and since that time at least 3 different papers have been published on the topic. In addition to being a μ-agonist, meperidine also has built-in affinity for the SERT and to a lesser extent the DAT. In consonance with the studies by H.M. Deutsch, et al. the authors were interested in investigating whether this activity at the DAT can be modulated in ways that might potentially lead to novel compounds with the aim of treating cocaine addiction, and thus this work was also funded by NIDA.

[edit] QSAR 1

(S.A. Lomenzo, et al.)[1][2]

In the first QSAR investigative efforts was purely in exploring how changing the nature of the aromatic substituents alters monoamine reuptake inhibitor affinities. From the table provided, it should impress on the reader that the m,p-Cl2 substitution pattern yields the most potent DARI, whereas the β-naphthyl aromatic nucleus gives the strongest and most selective 5-HT reuptake inhibitor. All of the compounds are more potent 5-HTergics than DAergics though. Moreover in behavioral activity studies, none of the compounds would substitute for cocaine in mice, and they were also inactive as LMA stimulants. This is in direct contrast to the methylphenidate analogs which more convincingly displayed cocaine-like traits. Indeed, the results of the research here was more of relevance to the QSAR of SSRI type compounds than meeting the structural requirements needed for the creation of psychostimulants, respectively.

In Vitro Data for Meperidine Analogs with Tritiated Radiotracers.
Compound DAT / SERT / Opioid (Ki, μM) and Dopamine (IC50, μM) Uptake Ratio
E Ar [3H]WIN 35,428 [3H]Paroxetine [3H]DAMGO [3H]Dopamine DAT/SERT μ/DAT μ/SERT
CO2Et Ph 17.8 ± 2.7 .413 ± .044 .92 12.6 ± 1.2 43.1 .052 2.13
CN p-F 45† 10.1 ± .4 15† 8† nd nd nd
CN p-Cl 22.0 ± 10.1 5.11 ± .59 36.8 (51)† 36† 4.31 1.67 .18
CN p-I 8.34 ± .67 .430 ± .0034 17.3 (61)† 36.7 ± 1.3 19.4 2.07 40.2
CN p-Me 41.8 ± 6.1 13.7 ± .4 40.6 (46)† 22† 3.05 .97 2.96
CN m,p-Cl2 2.67 ± .24 .805 ± .12 40.0 (46)† 11.1 ± 1.2 3.32 15.0 49.7
CN β-Naph 2.36 ± .66 .125 ± .022 15.4 (61)† 21.8 ± 1.2 18.9 6.53 123
CO2Et p-F 10.7 ± 2.3 .308 ± .026 1.47 47† 34.7 .14 4.77
CO2Et p-Cl 4.10 ± 1.27 .277 ± .040 4.41 26.9 ± 1.2 14.8 1.08 15.9
CO2Et p-I 3.25 ± .20 .0211 ± .0024 2.35 11.1 ± 1.2 155 .72 111
CO2Et p-Me 12.4 ± 5.2 1.61 ± .11 2.67 76.2 ± 1.2 7.69 .22 1.66
CO2Et m,p-Cl2 .125 ± .015 .0187 ± .0026 2.04 1.40 ± 1.25 6.68 16.3 109
CO2Et β-Naph 1.14 ± .38 .0072 ± .0001 2.03 11.6 ± 1.3 158 1.78 282
All values are the mean ± SEM of three experiments performed in triplicate. † Percent inhibition at highest dose tested (100μM).

Upon inspection of the above table, the reader should also be notice the almost neglgible affinity of any of the compounds for the NET, although it is not felt that this is a likely explanation for the lack of LMA. It is possible that lack of affinity for σ-receptrors might help explain lack of LMA, although this is insufficiently proven. The authors speculated that underlying residual activity at μ-opioid receptors can be used as an explanation, but this is not particularly marked, and in any event morphine can cause hyperlocomotion?

[edit] QSAR 2

(Jill Rhoden et, al.)[3]

Merperidine was initially found to be selective for the SERT over the DAT. Further exploration of various aryl-substituted piperidine analogs revealed that although DAT affinity of these compounds could be enhanced, high SERT affinity and selectivity predominated throughout the series. "Effects of the aryl substituent on DAT affinity of meperidine analogs paralleled the SAR previously reported for PT's." From the SAR of the meperidine analogs, the m,p-Cl2 analog was identified as an important moiety for molecular recognition at the DAT. However, even though this analog had the greatest DAT affinity in the whole series, it was still marginally SERT selective, suggesting that the 4,4-disubstituted piperidine meperidine scaffold is intrinsically SERT selective.

All the further analogs in the second QSAR study are based around the m,p-Cl2 phenyl substitution pattern. A number of different functional groups were used in lieu of the ethyl ester at the 4 position to further clarify the consequence that different subsitution patterns have on the SERT/DAT affinity ratio. A selection of different alkyl esters are shown for demonstration purposes in the attached table:

m,p-Cl2 merperidine ester derivatives
R CFT nM Para nM Ratio
Et 125 18.7 6.7
Me 383 15.4 25
n-Pr 449 16.4 27
i-Pr 271 43.3 6.3
n-Bu 864 16.0 54
n-Pen 283 44.3 6.4

In conclusion, while it was possible to 'design-out' DAT affinity, no such substitution pattern was discovered in either of the two QSAR studies providing a ligand with a DAT affinity exceeding the SERT affinity. It is suggested to the reader that the m-chlorophenyl ring should have been considered in view of the effect that this has been shown to have in some of the other literature on monoamine reuptake inhibitors (see for example Yardley, et al. 1990). The bottom line is that these ligands may be of value in the design of SSRIs but are not LMA stimulants that can be made to reliably substitute for cocaine.

Another remaining avenue for exploration is provided on the grounds of Meltzer, et al. in the field of PT's.[cit] Here it was discovered that while the nitrogen in these alkaloids provided ligands with the highest affinity, carbon, oxygen and even sulfur could be used in lieu of this and would still retain inhibitory activity. The relevence of this is that the N-demethyl metabolite of meperidine is toxic and accumulates upon repeat dosing.[cit] Replacing this would therefore provide a means of counteracting this problem. Also, the ester in meperidine is readily hydrolyzed. Other non-hydrolyzable functional groups at the 4-position can serve as a method for producing compounds with a longer half-life. Also consider the compound ketobemidone which is closely related to meperidine in terms of both structure and effects.

[edit] References

  1. ^ [1]Stacey Lomenzo, et al. (2005) J. Med. Chem. 48(5); 1336-1343.
  2. ^ [2]Stacey Lomenzo, et al. (1999) Bioorganic & Medicinal Chemistry Letters, Volume 9, Issue 23, Pages 3273-3276
  3. ^ [3]Jill B. Rhoden, et al. (2005) Bioorganic & Medicinal Chemistry Volume 13, Issue 19, Pages 5623-5634.