Design, synthesis, and structure-activity relationship studies of himbacine derived muscarinic receptor antagonists

doi:10.1016/S0960-894X(99)00101-8

Bioorganic & Medicinal Chemistry Letters

Volume 9, Issue 6, 22 March 1999, Pages 901-906

This paper is dedicated to the memory of Professor Sir Derek Barton

https://doi.org/10.1016/S0960-894X(99)00101-8 Get rights and content

Abstract

A parallel synthesis of racemic himbacine analogs was carried out by N-alkylation of various commercially available cyclic amine derivatives with the alkylating agent 4 which bears the tricyclic unit of himbacine. Several of these analogs have potency comparable to that of himbacine, albeit lacking the desired selectivity. Structure-activity relationship studies support the existence of a hydrophobic pocket in the receptor where the piperidine ring of dihydrohimbacine binds.

The intermediate (±)-4, which contains the tricyclic core of himbacine, was converted to various racemic himbacine analogs (3) using parallel synthesis. In cloned human muscarinic receptors, several of these compounds showed K_i values comparable to that of himbacine.

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Because oxotremorine-M had no significant effect on the amplitude of sEPSCs, only the data showing the effects of the drug on the frequency of sEPSCs are presented in the sections below. We next used himbacine, an M2/M4 subtype-preferring antagonist (18, 19, 25–27), to determine the potential role of the M2/M4 subtypes in the inhibitory effect of oxotremorine-M on sEPSCs in WT mice. The effective concentration of himbacine has been determined in our previous studies (18, 19, 25).
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Design, synthesis, and structure-activity relationship studies of himbacine derived muscarinic receptor antagonists

Abstract

Am. J. Geriatr. Psychiatry

Am. J. Geriatr. Psychiatry

Brain Res.

Life Sci.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Eur. J. Pharmacol.

Tetrahedron Lett.

Tetrahedron Lett.

Tetrahedron Lett.

Neuroscience Methods

Pharm. Res.

Neurology

J. Pharmacol. Exp. Ther.