ANALOGS 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 th e capsaicin molecule have been incorporated into a series of vanillyla mides and vanillylthioureas. These compounds have been tested in an in vitro assay for agonism (Ca-45(2+) influx into dorsal root ganglia ne urones), previously shown to be predictive of analgesic activity. The results of this study have established the requirement for a hydrophob ic substituent of limited size (molar refractivity, MR, <55) in order to obtain high potency. Combination of the information gained here abo ut the ''C-region'' of the capsaicin molecule with the studies describ ed in the preceding two papers provides a rational basis for the desig n of compounds of increased potency.