Synthesis and pharmacological characterization of new tetrahydrofuran based compounds as conformationally constrained histamine receptor ligands

Abstract

A series of tetrahydrofuran based compounds with a bicyclic core that provides conformational restriction were synthesized and investigated by radioligand displacement studies and functional [³⁵S]GTPγS binding assays at the human histamine receptor (hHR) subtypes. The amines 8a and 8b ((1S,3R,5S,6R)- and ((1S,3S,5S,6R)-3-(1H-imidazol-5-yl)-2-oxabicyclo[3.1.0]hexan-6-yl)methanamine), exhibited submicromolar K_i values at the hH₃R with 10-fold higher affinities than their corresponding (6S)-epimers and 25- and >34-fold selectivity over the hH₄R, respectively. Both compounds act as neutral antagonists at the hH₃R with K_B values of 181 and 32 nM, respectively. The cyanoguanidines of the imidazole series and the oxazole analogues turned out to be inactive at all hHR subtypes.