Influence of pH on the binding of diphenylmethylenepiperidines by 5-HT2B receptors in rat stomach fundus.

Cyproheptadine is one of the compounds exhibiting the highest activity at 5-HT2B receptors. In a previous work we analysed the relevance of the amino group in diphenylmethylenepiperidines (DPMP), which are open cyproheptadine analogues. Only compounds containing N-H or N-methyl motifs, showed significant 5-HT2B activity. Surprisingly, the corresponding quaternary ammonium salt demonstrated a total lack of activity. Therefore, the question arises whether protonation favours the interaction of these compounds with 5-HT2B receptors. Consequently, we studied the protonation influence (by varying the pH of the medium) on the antagonism of serotonin by some cyproheptadine analogues in rat stomach fundus. The main results were: 1) N-protonation increases the activity of DPMPs. 2) Alkaline pH facilitates the occurrence of a non-surmountable antagonism. 3) The contrast between the activity of protonated DPMPs and the lack of activity of the corresponding quaternary ammonium cation, suggests either that the latter is prevented from acting by steric hindrance, or that the mechanism by which protonation may increase the activity depends not only on the charge of the proton, but also on its ability to form hydrogen bonds.