Phenoxybenzamine
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|---|---|
| Systematic (IUPAC) name | |
| (RS)-N-benzyl-N-(2-chloroethyl)-1-phenoxypropan-2-amine | |
| Clinical data | |
| Trade names | Dibenzyline |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a682059 |
| Pregnancy cat. | C (U.S.) |
| Legal status | ? |
| Routes | Oral |
| Pharmacokinetic data | |
| Half-life | 24 hours |
| Identifiers | |
| CAS number | 59-96-1  |
| ATC code | C04AX02 |
| PubChem | CID 4768 |
| DrugBank | DB00925 |
| ChemSpider | 4604 |
| UNII | 0TTZ664R7Z |
| KEGG | D08358 |
| ChEMBL | CHEMBL753 |
| Chemical data | |
| Formula | C18H22ClNO |
| Mol. mass | 303.826 g/mol |
| SMILES
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Phenoxybenzamine (marketed under the trade name Dibenzyline) is a non-selective, irreversible alpha antagonist.
Uses
It is used in the treatment of hypertension, and specifically that caused by pheochromocytoma. It has a slower onset and a longer lasting effect compared with other alpha blockers.
It was also the first alpha blocker to be used for treatment of benign prostatic hyperplasia,[1] although it is currently seldom used for that indication due to unfavourable side effects.
It has been used in the treatment of hypoplastic left heart syndrome.[2]
It is also used in complex regional pain syndrome type 1 due to its anti-adrenergic affects. It has shown to be beneficial if used in the first 3 months of the CRPS diagnosis.
Investigational
Phenoxybenzamine has long been known to block ejaculation without affecting semen quality or ability to achieve orgasm, which could make it an effective male contraceptive. This effect is completely reversible, and is believed to be the result of alpha-1 adrenoceptor blockade in the longitudinal muscles of the vas deferens.[3][4][5] As of 2008, research was underway to identify possible drug candidates that share this effect but act specifically on the reproductive tract, unlike phenoxybenzamine.[3]
Chemistry
Phenoxybenzamine, N-(2-chloroethyl)-N-(1-methyl-2-phenoxyethyl)benzylamine, is synthesized by reacting phenol with propylenoxide, which forms 1-phenoxy-2-propanol, the chlorination of which with thionyl chloride gives 1-phenoxy-2-propylchloride. Reacting this with 2-aminoethanol leads to formation of 1-phenoxy-2-(2-hydroxyethyl)aminopropane. Alkylation of the secondary amino group gives N-(2-hydroxyethyl)-N-(1-methyl-2-phenoxyethyl)benzylamine, the
hydroxyl group of which is chlorinated using thionyl chloride, giving phenoxybenzamine
- J.F. Kerwin, G.E. Ullyot, U.S. Patent 2,599,000 (1952).
Pharmacology
Phenoxybenzamine is used as an anti-hypertensive due to its efficacy in reducing the vasoconstriction caused by epinephrine (adrenaline) and norepinephrine. Phenoxybenzamine forms a permanent covalent bond with adrenergic receptors. Based on known information about the structures of these receptors, it likely involves attack by the cysteine at position 3.36 in transmembrane helix 3 to form a stable linkage.[6] Thus, it remains permanently bound to the receptor, preventing adrenaline and noradrenaline from binding. This causes vasodilatation in blood vessels, due to its antagonistic effect at the alpha-1 adrenoceptor found in the walls of blood vessels, resulting in a drop in blood pressure. A side effect of phenoxybenzamine is reflex tachycardia.
It will also affect the postsynaptic alpha 1 and 2 receptors in the nervous system, and so reduce sympathetic activity. This results in further vasodilation, pupil constriction, an increase in GI tract motility and secretions, and glycogen synthesis.
It also has partial agonist/antagonist properties at the serotonin 5-HT2A receptor. Due to its 5-HT2A antagonism, it is useful in the treatment of carcinoid tumor, a neoplasm that secretes large amounts of serotonin and causes diarrhea, bronchoconstriction, and flushing.[7]
References
- ↑ Caine M, Perlberg S, Meretyk S (1978). "A placebo-controlled double-blind study of the effect of phenoxybenzamine in benign prostatic obstruction". British journal of urology 50 (7): 551–4. doi:10.1111/j.1464-410X.1978.tb06210.x. PMID 88984.
- ↑ Guzzetta NA (August 2007). "Phenoxybenzamine in the treatment of hypoplastic left heart syndrome: a core review". Anesth. Analg. 105 (2): 312–5. doi:10.1213/01.ane.0000275185.44796.92. PMID 17646482.
- ↑ 3.0 3.1 Aitken RJ, Baker MA, Doncel GF, Matzuk MM, Mauck CK, Harper MJ (April 2008). "As the world grows: contraception in the 21st century". J Clin Invest 118 (4): 1330–43. doi:10.1172/JCI33873. PMC 2276786. PMID 18382745.
- ↑ Kjaergaard N, Kjaergaard B, Lauritsen JG (June 1988). "Prazosin, an adrenergic blocking agent inadequate as male contraceptive pill". Contraception 37 (6): 621–9. doi:10.1016/0010-7824(88)90008-X. PMID 2899490.
- ↑ Homonnai ZT, Shilon M, Paz GF (May 1984). "Phenoxybenzamine—an effective male contraceptive pill". Contraception 29 (5): 479–91. doi:10.1016/0010-7824(84)90022-2. PMID 6430643.
- ↑ Frang H, Cockcroft V, Karskela T, Scheinin M, Marjamäki A (2001). "Phenoxybenzamine binding reveals the helical orientation of the third transmembrane domain of adrenergic receptors". J. Biol. Chem. 276 (33): 31279–84. doi:10.1074/jbc.M104167200. PMID 11395517.
- ↑ Katzung, Trevor et al. Pharmacology Board Review. p.153. Mcgraw Hill, 2007.
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