Synthesis and structure-activity relationships of conformationally constrained histamine H(3) receptor agonists

Ruengwit Kitbunnadaj; Obbe P Zuiderveld; Iwan J P De Esch; Roeland C Vollinga; Remko Bakker; Martin Lutz; Anthony L Spek; Emile Cavoy; Marie-France Deltent; Wiro M P B Menge; Henk Timmerman; Rob Leurs

doi:10.1021/jm030905y

Synthesis and structure-activity relationships of conformationally constrained histamine H(3) receptor agonists

J Med Chem. 2003 Dec 4;46(25):5445-57. doi: 10.1021/jm030905y.

Authors

Ruengwit Kitbunnadaj¹, Obbe P Zuiderveld, Iwan J P De Esch, Roeland C Vollinga, Remko Bakker, Martin Lutz, Anthony L Spek, Emile Cavoy, Marie-France Deltent, Wiro M P B Menge, Henk Timmerman, Rob Leurs

Affiliation

¹ Leiden/Amsterdam Center of Drug Research (LACDR), Department of Pharmacochemistry, Faculty of Chemistry, Vrije Universiteit, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.

PMID: 14640553
DOI: 10.1021/jm030905y

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Binding, Competitive
Cell Line
Colorimetry
Crystallography, X-Ray
Cyclic AMP / metabolism
Histamine / chemistry
Histamine / pharmacology
Histamine Agonists / chemical synthesis*
Histamine Agonists / chemistry
Histamine Agonists / pharmacology
Histamine Antagonists / chemical synthesis
Histamine Antagonists / chemistry
Histamine Antagonists / pharmacology
Humans
Imidazoles / chemical synthesis
Imidazoles / chemistry
Imidazoles / pharmacology
Ligands
Molecular Conformation
Piperidines / chemical synthesis
Piperidines / chemistry
Piperidines / pharmacology
Pyrrolidines / chemical synthesis
Pyrrolidines / chemistry
Pyrrolidines / pharmacology
Radioligand Assay
Receptors, G-Protein-Coupled*
Receptors, Histamine / drug effects
Receptors, Histamine / metabolism
Receptors, Histamine H3 / drug effects*
Receptors, Histamine H3 / metabolism
Receptors, Histamine H4
Stereoisomerism
Structure-Activity Relationship

Substances

HRH4 protein, human
Histamine Agonists
Histamine Antagonists
Imidazoles
Ligands
Piperidines
Pyrrolidines
Receptors, G-Protein-Coupled
Receptors, Histamine
Receptors, Histamine H3
Receptors, Histamine H4
4-(1H-imidazol-4-ylmethyl)piperidine
Histamine
Cyclic AMP