title: Analogues of capsaicin with agonist activity as novel analgesic agents; structure-activity studies. 2. The amide bond "B-region".
abstract: A series of compounds incorporating replacements for the amide bond "B-region" moiety of capsaicin have been synthesized, including vanillylamides and esters, homovanillic acid amides and esters, ureas, and thioureas. These have been tested in an in vitro assay for agonism (45Ca2+ influx into dorsal root ganglia neurones), which is predictive of analgesic activity, to investigate the requirements in this region of capsaicin for activity. N-(4-Hydroxy-3-methoxybenzyl)-N'-octylthiourea (14a) emerged as the most potent analogue (EC50 = 0.06 microM). An operational model based on multiple hydrogen-bonding interactions is proposed to explain the structure-activity profile observed. In combination with studies on the other regions of the capsaicin molecule these results describe a picture of the molecular interactions of capsaicin with its putative receptor.
authors.affiliation: Sandoz Institute for Medical Research, Gower Place, London, England.
authors.forename: C S
authors.initials: CS
authors.lastname: Walpole
authors.forename: R
authors.initials: R
authors.lastname: Wrigglesworth
authors.forename: S
authors.initials: S
authors.lastname: Bevan
authors.forename: E A
authors.initials: EA
authors.lastname: Campbell
authors.forename: A
authors.initials: A
authors.lastname: Dray
authors.forename: I F
authors.initials: IF
authors.lastname: James
authors.forename: K J
authors.initials: KJ
authors.lastname: Masdin
authors.forename: M N
authors.initials: MN
authors.lastname: Perkins
authors.forename: J
authors.initials: J
authors.lastname: Winter
mesh_terms: D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002120:Calcium Channel Agonists / Q000737:chemistry / Q000494:pharmacology*; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000737:chemistry; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D007082:Ileum; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D002120:Calcium Channel Agonists; D002211:Capsaicin; D002118:Calcium