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

Abstract

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.

Identification and Characterization of ZEL-H16 as a Novel Agonist of the Histamine H3 Receptor

“…Consequently, many imidazole-based histamine H3 receptor agonists also possess a high affinity at the H4 receptor. As one of the most potent and selective H3 agonist, immepip also shows reasonable potency for the histamine H4 receptor with pKi values of 7.66 [43]. In the current study, we have identified a new non-imidazole based H3 agonist, ZEL-H16, which exhibited approximately 20-fold higher affinity for human H3R as compared to histamine.…”

Histamine H3 Antagonists as Wake-Promoting and Pro-Cognitive Agents

“…One well-characterized example is Immepip (9) (pK i =9.32). Immepip was found to be a histamine H 3 agonist and the authors suggest that histamine H 3 agonists might be useful for the treatment of inflammatory disorders [43]. With few exceptions [44,45], most of the more recent literature focuses on non-imidazole-based ligands, likely due to the metabolic liabilities generally associated with the imidazole moiety.…”

Synthesis and structure–activity relationships of indole and benzimidazole piperazines as histamine H4 receptor antagonists

“…The intermediate 24 was transformed to the ketone 25 via a Swern oxidation reaction 21. The reaction of SEM-protected intermediates 24 and 25 with tetrabutylammonium fluoride monohydrate in the presence of ethylenediamine resulted in good yields of the deprotected indoles 10 and 11, respectively 22.…”