Vol. 283, Issue 3, 1534-1543, 1997

Novel Qualitative Structure-Activity Relationships for the Antinociceptive Actions of H₂ Antagonists, H₃ Antagonists and Derivatives¹

L. B. Hough, J. W. Nalwalk, B. Y. Li, R. Leurs, W.M.P.B. Menge, H. Timmerman, M. E. Carlile, C. Cioffi and M. Wentland

Department of Pharmacology and Neuroscience, Albany Medical College, Albany, New York (L.B.H., J.W.N., B.Y.L, M.E.C.), Leiden/Amsterdam Center for Drug Research, Department of Pharmacochemistry, Vrije University, Amsterdam, The Netherlands (R.L., W.M.P.B.M., H.T.) and the Department of Chemistry, Rensselaer Polytechnic Institute, Troy, New York (C.C., M.W.)

Recent studies have shown that cimetidine, burimamide and improgan (also known as SKF92374, a cimetidine congener lacking H₂ antagonist activity) induce antinociception after intracerebroventricular administration in rodents. Because these substances closely resemble the structure of histamine (a known mediator of some endogenous analgesic responses), yet no role for known histamine receptors has been found in the analgesic actions of these agents, the structure-activity relationships for the antinociceptive effects of 21 compounds chemically related to H₂ and H₃ antagonists were investigated in this study. Antinociceptive activity was assessed on the hot-plate and tail-flick tests after intracerebroventricular administration in rats. Eleven compounds induced time-dependent (10-min peak) and dose-dependent antinociceptive activity with no observable behavioral impairment. ED₅₀ values, estimated by nonlinear regression, were highly correlated across nociceptive assays (r² = 0.98, n = 11). Antinociceptive potencies varied more than 6-fold (80-464 nmol), but were not correlated with activity on H₁, H₂ or H₃ receptors. Although highly potent H₃ antagonists such as thioperamide lacked antinociceptive activity, homologs of burimamide and thioperamide containing N-aromatic substituents retained H₃ antagonist activity and also showed potent, effective analgesia. A literature review of the pharmacology of these agents did not find a basis for their antinociceptive effects. Taken with previous findings, the present results suggest: 1) these compounds act on the brain to activate powerful analgesic responses that are independent of known histamine receptors, 2) the structure-activity profile of these agents is novel and 3) brain-penetrating derivatives of these compounds could be clinically useful analgesics.