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

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 transcyclopropylhistamine enantiomers were tested for their activity and affinity on the histamine H 3 receptor. (1S,2S)-Cyclopropylhistamine (VUF 5297) acts as an agonist both on the rat cortex (pD 2 ) 7.1; R ) 0.75) and on guinea pig jejunum (pD 2 ) 6.6; R ) 0.75). Its enantiomer, (1R,2R)-cyclopropylhistamine (VUF 5296), is about 1 order of magnitude less active. Both enantiomers show weak activity on H 1 and H 2 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 H 3 receptor ligands.

The Histamine H3Receptor: Structure, Pharmacology, and Function

“…The first highly selective and potent H 3 R ligands were the agonist RAMH (R-a-methylhistamine) and the antagonist thioperamide, and the differences in the affinity and potency of the ligand enantiomers demonstrated the stereoselectivity of the H 3 R (Arrang et al, 1987a;De Esch et al, 1999;Kovalainen et al, 1999). The replacement of the histamine amine group by an isothiourea group led to the very potent and selective H 3 R agonist imetit (Garbarg et al, 1992), and other histamine analogs with a piperidine ring in the side chain, such as immepip, showed improved affinity and efficacy at the H 3 R ( Fig.…”

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

“…Compound 9 was synthesized (Scheme 1) from a known intermediate, (()-trans-ethyl 2-(1-triphenylmethylimidazol-4-yl)cyclopropanecarboxylate. 30 Reduction of the intermediate using LiAlH 4 gave an alcohol (21), which was subsequently transformed into amine (9) via a Mitsunobu reaction and hydrolysis in a good yield (90%). 31,32 Compounds 12a-c were prepared according to Scheme 2.…”

A Qualitative Model for the Histamine H3 Receptor Explaining Agonistic and Antagonistic Activity Simultaneously

“…To validate our model, both enantiomers of the small and rigid compound trans-cyclopropylhistamine were synthesized and the distinct stereoisomers were tested for their H 3 activity [41] . The enantiomers, differing significantly in pharmacological activity, give a proper interaction with the Asp side chain in the all trans conformation (validating the position of this receptor site point).…”