Analogues of capsaicin with agonist activity as novel analgesic agents; structure-activity studies. 2. The amide bond "B-region".
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.
Walpole
C S
CS
Sandoz Institute for Medical Research, Gower Place, London, England.
Wrigglesworth
R
R
Bevan
S
S
Campbell
E A
EA
Dray
A
A
James
I F
IF
Masdin
K J
KJ
Perkins
M N
MN
Winter
J
J
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
D000700:Analgesics; D002120:Calcium Channel Agonists; D002211:Capsaicin; D002118:Calcium