Characterization of the binding site of the histamine H3 receptor. 1. Various approaches to the synthesis of 2-(1H-imidazol-4-yl)cyclopropylamine and histaminergic activity of (1R,2R)- and (1S,2S)-2-(1H-imidazol-4-yl)-cyclopropylamine

I J De Esch; R C Vollinga; K Goubitz; H Schenk; U Appelberg; U Hacksell; S Lemstra; O P Zuiderveld; M Hoffmann; R Leurs; W M Menge; H Timmerman

doi:10.1021/jm9810912

Characterization of the binding site of the histamine H3 receptor. 1. Various approaches to the synthesis of 2-(1H-imidazol-4-yl)cyclopropylamine and histaminergic activity of (1R,2R)- and (1S,2S)-2-(1H-imidazol-4-yl)-cyclopropylamine

J Med Chem. 1999 Apr 8;42(7):1115-22. doi: 10.1021/jm9810912.

Authors

I J De Esch¹, R C Vollinga, K Goubitz, H Schenk, U Appelberg, U Hacksell, S Lemstra, O P Zuiderveld, M Hoffmann, R Leurs, W M Menge, H Timmerman

Affiliation

¹ Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Department of Pharmacochemistry, Faculty of Chemistry, Vrije Universiteit, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.

PMID: 10197956
DOI: 10.1021/jm9810912

Abstract

Various approaches to the synthesis of all four stereoisomers of 2-(1H-imidazol-4-yl)cyclopropylamine (cyclopropylhistamine) are described. The rapid and convenient synthesis and resolution of trans-cyclopropylhistamine is reported. The absolute configuration of its enantiomers was determined by single-crystal X-ray crystallographic analysis. The distinct trans-cyclopropylhistamine enantiomers were tested for their activity and affinity on the histamine H3 receptor. (1S,2S)-Cyclopropylhistamine (VUF 5297) acts as an agonist both on the rat cortex (pD2 = 7.1; alpha = 0.75) and on guinea pig jejunum (pD2 = 6.6; alpha = 0.75). Its enantiomer, (1R, 2R)-cyclopropylhistamine (VUF 5296), is about 1 order of magnitude less active. Both enantiomers show weak activity on H1 and H2 receptors. All synthetic attempts to cis-cyclopropylhistamine were unsuccessful. Nevertheless, the results of this study provide an ideal template for molecular modeling studies of histamine H3 receptor ligands.

Publication types

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

MeSH terms

Animals
Binding Sites
Binding, Competitive
Cerebral Cortex / metabolism
Crystallography, X-Ray
Cyclopropanes / chemical synthesis*
Cyclopropanes / chemistry
Cyclopropanes / metabolism
Cyclopropanes / pharmacology
Guinea Pigs
Heart Rate / drug effects
Histamine / analogs & derivatives*
Histamine / chemical synthesis
Histamine / chemistry
Histamine / metabolism
Histamine / pharmacology
Histamine Agonists / chemical synthesis
Histamine Agonists / chemistry
Histamine Agonists / metabolism
Histamine Agonists / pharmacology
Ileum / drug effects
Ileum / physiology
In Vitro Techniques
Jejunum / drug effects
Jejunum / physiology
Models, Molecular
Muscle Contraction / drug effects
Muscle, Smooth / drug effects
Muscle, Smooth / physiology
Norepinephrine / metabolism
Rats
Receptors, Histamine H1 / drug effects
Receptors, Histamine H2 / drug effects
Receptors, Histamine H3 / metabolism*
Stereoisomerism
Structure-Activity Relationship

Substances

Cyclopropanes
Histamine Agonists
Receptors, Histamine H1
Receptors, Histamine H2
Receptors, Histamine H3
VUF 5296
Histamine
Norepinephrine