Molecular properties of the histamine H2-receptor. Covalent inhibition by tetraamine disulfides

A series of tetraamine disulfides related to benextramine (an alpha-adrenoreceptor and H2-receptor antagonist) in which the distance between the inner and the outer nitrogens were changed from five to nine methylenes has been studied. Both effects of the displacement of the disulfide bridge by two methylenes and those of the progressive removal of two of the four nitrogens on the pharmacological profile have been assessed. Peak potency appeared to be associated with eight methylenes between the inner and the outer nitrogens and to four cationic charges as in the most active analogue 4 which was also investigated to assess its receptor specificity towards histamine H1 and muscarinic M2 and M3 receptors. The finding that the carbon analogue 11 (two methylenes for the disulfide bridge) was devoid of activity is consistent with the hypothesis that histamine H2-receptor inhibition is the result of a covalent bond formation by a way of a disulfide-thiol interchange reaction between the disulfide moiety of tetraamine disulfides and a receptor thiol group. However, the possibility that tetraamine disulfides may not act at the H2-receptor but beyond the receptor cannot be excluded.