Immepip, a conformationally constrained analogue of the histamine congener imbutamine, shows high affinity and functional activity on the human H 3 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 H 3 receptor and the closely related H 4 receptor. In the series of piperidine containing analogues, immepip was found to be the most potent H 3 receptor agonist, whereas its propylene analogue 13a was identified as a high-affinity neutral antagonist for the human H 3 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 H 3 and H 4 receptor.

In this study, the piperidine ring of immepip and its analogues was replaced by a rigid heterocyclic pyridine ring. Many compounds in the series exhibit high affinity and agonist activity at the human histamine H(3) receptor. Particularly, the 4-pyridinyl analogue of immepip (1c, immethridine) is identified as a novel potent and highly selective histamine H(3) receptor agonist (pK(i) = 9.07, pEC(50) = 9.74) with a 300-fold selectivity over the closely related H(4) receptor.