NOVEL QUALITATIVE STRUCTURE-ACTIVITY-RELATIONSHIPS FOR THE ANTINOCICEPTIVE ACTIONS OF H-2 ANTAGONISTS, H-3 ANTAGONISTS AND DERIVATIVES

Recent studies have shown that cimetidine, burimamide and improgan (al so known as SKF92374, a cimetidine congener lacking H-2 antagonist act ivity) induce antinociception after intracerebroventricular administra tion in rodents. Because these substances closely resemble the structu re of histamine (a known mediator of some endogenous analgesic respons es), yet no role for known histamine receptors has been found in the a nalgesic actions of these agents, the structure-activity ly relationsh ips for the antinociceptive effects of 21 compounds chemically related to H-2 and H-3 antagonists were investigated in this study. Antinocic eptive activity was assessed on the hot-plate and tail-flick tests aft er intracerebroventricular administration in rats. Eleven compounds in duced time-dependent (IO-min peak) and dose-dependent antinociceptive activity with no observable behavioral impairment. ED50 values, estima ted by nonlinear regression, were highly correlated across nociceptive assays (r(2) = 0.98, n = 11). Antinociceptive potencies varied more t han 6-fold (80-464 nmol), but were not correlated with activity on H-1 , H-2 or H-3 receptors. although highly potent H-3 antagonists such as thioperamide lacked antinociceptive activity, homologs of burimamide and thioperamide containing N-aromatic substituents retained H-3 antag onist activity and also showed potent, effective analgesia. A literatu re review of the pharmacology of these agents did not find a basis for their antinociceptive effects. Taken with previous findings, the pres ent results suggest: I) these compounds act on the brain to activate p owerful analgesic responses that are independent of known histamine re ceptors, 2) the structure-activity profile of these agents is novel an d 3) brain-penetrating derivatives of these compounds could be clinica lly useful analgesics.