The EHT calculated trans/gauche conformer population ratios of a series of methylhistamines are compared with their H1/H2 histamine receptor agonist activity ratios. Conformer ratios for α- and β-methyl- and N, N-dimethylhistamines are predicted to be quite different, respectively 0.1,0.02, and 4; yet none of these compounds show significant biological selectivity. On the other hand, 2-and 4-methylhistamines have very similar trans/gauche conformational preferences but show a dramatic 1000-fold difference in their activity ratios. Thus, side-chain rotamer preference does not appear to determine whether these conformationally mobile derivatives distinguish between H1 and H2 receptors. However, an altered rotamer preference is accompanied by reduced activity and the results are consistent with a trans conformer possibly being involved at both types of histamine receptor. © 1973, American Chemical Society. All rights reserved.
