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.

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We describe development of scalable syntheses of novel oxindole-type SV2A ligands with improved potency towards seizure suppression.

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