Gary Johansson

3-Heteroarylquinuclidin-2-ene derivatives as muscarinic antagonists: synthesis, structure-activity relationships and molecular modelling.

Publisher Summary This chapter examines a variety of C-5 substituted analogs in an attempt to determine what physicochemical properties influence the M 1 receptor affinity. The new compounds are tested in receptor binding and functional assays as previously reported. A series of achiral muscarinic antagonists with structures related chiral quinuclidine derived agonists. The most potent antagonist is the 2-benzofuranyl derivative. Replacing the 2-benzofuranyl with a 3-benzofuranyl-, furanyl-, thienyl-, 2- or 3-benzothienyl, or a 2-benzoxazolyl moiety gives less potent antagonists. In general, the antagonists display low selectivity for the investigated muscarinic receptor subtypes (M 1 , M 2 and M 3 ). An analysis of the structure-affinity relationships among the benzo-fused five-membered heteroaromatic analogs demonstrates that the magnitude of the negative electrostatic potential in the benzene moiety correlates with M 1 receptor affinity. In an attempt to determine what physicochemical properties of the substituted benzofuran derivatives influence the M 1 -receptor affinity, the chapter performs a QSAR analysis of the 9 derivatives.

Quinuclidin-2-ene-based muscarinic antagonists.

A series of achiral 3-heteroaryl substituted quinuclidin-2-ene derivatives and related compounds have been synthesized by facile methods. The compounds were evaluated for muscarinic and antimuscarinic properties in receptor binding studies using (-)-[3H]-QNB as the radioligand and in a functional assay using isolated guinea pig urinary bladder. 3-(2-Benzofuranyl)-quinuclidin-2-ene (15) displayed the highest M1-receptor affinity in the present series (Ki = 9.6 nM).