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 [ 35 S]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 hH 3 R with 10-fold higher affinities than their corresponding (6S)-epimers and 25-and >34-fold selectivity over the hH 4 R, respectively. Both compounds act as neutral antagonists at the hH 3 R 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.

Visible light-driven dearomative ring expansion of (aza)arenes to access dihydrofuran-based polycyclic compounds

“…This could offer a useful ring expansion approach to cycloheptatriene variants bearing the valuable dihydrofuran moiety 22–24 (Scheme 1E-1). If it is feasible, we wondered whether such intramolecular radical addition to olefins, instead of aza(arenes), could initiate a five-membered ring transition state, thereby facilitating the synthesis of the medically valuable dihydrofuran-based cyclopropanes 25,26 from 1,3-dienones via a predicable cascade diradical recombination pathway, with diradicals favored over carbenes as intermediates (Scheme 1E-2). The challenge of reactivity in both scenarios stems from the release of energy by the E / Z isomerization of the triplet enones, 27 a long-standing dilemma in developing practical synthetic methods.…”