Muscarinic Properties of Compounds Related to Arecaidine Propargyl Ester

Abstract

A series of new analogues of the arecaidine propargyl ester (CAS 35516-99-5), APE, 1a) with alcohols consisting of 4 or 5 carbon atoms were investigated at muscarinic receptor subtypes. The muscarinic activity of the quaternary and tertiary salts of the APE-related compounds were assayed on the isolated guinea-pig ileum (M3 receptor subtype) and guinea-pig left atria (M2 receptor subtype) as well as on rabbit isolated vas deferens (M1 receptor subtype). The structural variations made in the APE molecule, replacing the triple bond in the ester side chain with structures such as double bond, an allene moiety, a single bond, a cyclopropyl group or two triple bonds should alter the selectivity and potency in favour of the M2 subtype. Enhanced, though modest, selectivity for M2 receptors was achieved with the 2-butynyl ester 2a. The other structural variations resulted in a loss of potency, but not necessarily of efficacy.

Functional Characterization of Muscarinic Receptors in Human Schwann Cells

“…In the present study, it has not been possible to perform pharmacological competition studies with selective antagonists for muscarinic receptors considering the limited number of the cells obtained from the same patients. Albeit the APE-derived compounds were reported as preferential M1–M4 agonists [ 25 ], several structural variations of the molecules appeared to improve the selectivity for M2 receptor [ 26 , 27 ]. In particular, the M2 agonist APE has been largely characterized by our group by pharmacological competition studies performed in rat glial cells and DRG sensory neurons, clearly demonstrating that APE effects are largely counteracted only by gallamine, one of the preferential M2 receptor antagonist [ 8 , 28 ].…”

“…Human SCs were treated with M2 selective agonist arecaidine propargyl ester hydrobromide (APE, A140; Sigma-Aldrich) at the final concentration ranging from 25 to 100 µM. Albeit APE was reported as preferential M1–M4 agonist [ 25 ], several modifications of the molecule suggested a preferential agonistic effect on M2 receptor subtype [ 26 , 27 ]. Our works have been focused on the characterization of APE hydrobromide by pharmacological competition studies with M2 antagonists methoctramine or gallamine [ 8 , 17 , 32 ].…”