The profiles of human and primate [3H]Nα-methylhistamine binding differ from that of rodents

Characterization of the histamine H-3 receptor in rodent species has been extensive but limited characterization has been done with primate or human tissue. We have characterized the binding of [H-3]N-alpha-methylhistamine to cynomolgus monkey and human brain membranes to determine whether there are any significant differences among species' pharmacology. In monkey, [H-3]N-alpha-methylhistamine bound, in a guanine nucleotide-sensitive fashion, to an apparently homogeneous class of sites at equilibrium (K-D = 1.4 nM, B-max = 34 fmol/mg protein). The profile of binding was broadly similar to that of rodents, with a couple of significant differences. Most notably, the potency of the histamine H-3-receptor-specific antagonist thioperamide (K-i = 240 nM) was substantially less than reported for rodents and under assay conditions that yield a two-site curve fit in rodents only a single class of thioperamide binding sites was detected in monkey. Burimamide, however, yielded a two-site curve fit (K-iH = 6.7 nM, K-iL = 1100 nM) independent of the presence of sodium in the assay, as it does in rodents. Characterization of the human brain histamine H-3 receptor showed that it was similar to the monkey and not rodent receptor. Our findings indicate that differences between primate and rodent histamine H-3 receptors of potentially serious importance for the discovery of antagonists active in humans do exist. (C) 1999 Elsevier Science B.V. All rights reserved.