Analogues of capsaicin with agonist activity as novel analgesic agents; structure-activity studies. 3. The hydrophobic side-chain "C-region".
Structural variants of the hydrophobic side chain ("C region") of the capsaicin molecule have been incorporated into a series of vanillylamides and vanillylthioureas. These compounds have been tested in an in vitro assay for agonism (45Ca2+ influx into dorsal root ganglia neurones), previously shown to be predictive of analgesic activity. The results of this study have established the requirement for a hydrophobic substituent of limited size (molar refractivity, MR, < 55) in order to obtain high potency. Combination of the information gained here about the "C-region" of the capsaicin molecule with the studies described in the preceding two papers provides a rational basis for the design of compounds of increased potency.
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 / Q000494:pharmacology*; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; 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