Synthesis and Structure-Activity Relationships of Conformationally Constrained Histamine H3 Receptor Agonists.

Immepip, a conformationally constrained analogue of the histamine congener imbutamine, shows high affinity and functional activity on the human H3 receptor. Using histamine and its homologues as prototypes, other rigid analogues containing either a piperidine or pyrrolidine ring in the side chain were synthesized and tested for their activities at the human H3 receptor and the closely related H4 receptor. In the series of piperidine containing analogues, immepip was found to be the most potent H3 receptor agonist, whereas its propylene analogue 13a was identified as a high-affinity neutral antagonist for the human H3 receptor. Moreover, replacement of the piperidine ring of immepip by a pyrrolidine ring led to a pair of enantiomers that show a distinct stereoselectivity at the human H3 and H4 receptor.