Functionalized congener approach to muscarinic antagonists: analogues of pirenzepine

Journal of Medicinal Chemistry
Y KartonK A Jacobson

Abstract

The M1-selective muscarinic receptor antagonist pirenzepine 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one) was derivatized to explore points of attachment of functionalized side chains for the synthesis of receptor probes and ligands for affinity chromatography. The analogues prepared were evaluated in competitive binding assays versus [3H]-N-methylscopolamine at four muscarinic receptor subtypes (m1AChR-m4AChR) in membranes from rat heart tissue and transfected A9L cells. 9-(Hydroxymethyl)pirenzepine, 8-(methylthio)pirenzepine, and a series of 8-aminosulfonyl derivatives were synthesized. Several 5-substituted analogues of pirenzepine also were prepared. An alternate series of analogues substituted on the 4-position of the piperazine ring was prepared by reaction of 4-desmethylpirenzepine with various electrophiles. An N-chloroethyl analogue of pirenzepine was shown to form a reactive aziridine species in aqueous buffer yet failed to affinity label muscarinic receptors. Within a series of aminoalkyl analogues, the affinity increased as the length of the alkyl chain increased. Shorter chain analogues were generally much less potent than pirenzepine, and longer analogues (7-10 carbons) were roughly as potent as pirenzepine at m1 rece...Continue Reading

References

Dec 1, 1990·Archives of Biochemistry and Biophysics·M E OlahG L Stiles
Sep 15, 1990·Biochemical Pharmacology·A H NewmanP K Chiang
Oct 12, 1989·The New England Journal of Medicine·R K Goyal
Nov 1, 1988·Trends in Pharmacological Sciences·P J BarnesJ Maclagan
Sep 1, 1984·Proceedings of the National Academy of Sciences of the United States of America·A R HughesT K Harden

Citations

Jan 1, 1992·Life Sciences·J BaumgoldK A Jacobson
Mar 18, 2010·Assay and Drug Development Technologies·Kristin G HuwilerKurt W Vogel
Mar 15, 2005·The Journal of Pharmacology and Experimental Therapeutics·Dinesh GautamJürgen Wess

Related Concepts

Metazoa
Plasma Membrane
Antispasmodic Effect
Piperazines
Pirenzepin von ct
Muscarinic Acetylcholine Receptor
Scopolamine Derivatives
Structure-Activity Relationship
Skopyl
Rats, Laboratory

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