Replacement of imidazole by a piperidine moiety differentially affects the potency of histamine H3-receptor antagonists

We examined whether replacement of imidazole by a piperidine or pyrrolidine moiety will affect the potency and affinity of six H-3-receptor antagonists. Potencies were determined in superfused mouse brain cortex slices preincubated with [H-3]noradrenaline, in which the interaction of the antagonists with histamine with respect to its inhibitory effect on the electrically evoked tritium overflow was studied. Affinities were determined in mouse brain cortex membranes, using the radioligand [H-3]N-alpha-methylhistamine. The concentration-response curve of histamine for its effect on the evoked overflow from mouse brain cortex slices was shifted to the right by the 13 compounds under study. Replacement of the imidazole by a piperidine ring affected the pA(2) value as follows: thioperamide, -2.7 log units; clobenpropit, -1.9; proxyfan, -1.3; FUB 138, -1.2. Potency hardly changed (less than or equal to0.4 log units) when imidazole was replaced by piperidine in FUB 181 and by piperidine or pyrrolidine in FUB 153. Binding of [H-3]N-alpha-methylhistamine to mouse brain cortex membranes was inhibited monophasically by all compounds. The pK(i) values closely matched their pA2 values with three exceptions. The pKi values of proxyfan, FUB 138, and FUB 153 exceeded their respective pA2 values by about 1 log unit. To reveal a potential partial agonism, the effect of the three drugs on (1) the electrically evoked tritium overflow and (2) [S-35]GTPgammaS binding in mouse cortex preparations was determined. Proxyfan proved to be a partial agonist in both models (with intrinsic activities of 0.2 and 0.3, respectively) whereas FUB 138 and FUB 153 were devoid of agonistic effects. In conclusion, replacement of imidazole by piperidine or pyrrolidine affects the antagonist potencies of six H-3-receptor antagonists in a very different manner. The piperidine analogue of FUB 181 (with a pA(2) value as high as 7.7) may represent a lead for the development of non-imidazole H3-receptor antagonists. The discrepancy between the pK(i) and pA(2) values may be accounted for by partial agonism in the case of proxyfan but can, at present, not be satisfactorily explained with respect to FUB 138 and FUB 153.