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.