Different muscarine receptors mediate the prejunctional inhibition of [3H]-noradrenaline release in rat or guinea-pig iris and the contraction of the rabbit iris sphincter muscle

To investigate the muscarine receptor type mediating inhibition of [3H]-noradrenaline release from the isolated rat and guinea-pig iris we have determined the potency of antimuscarinic drugs to antagonize the methacholine-induced inhibition of [3H]-noradrenaline overflow evoked by field stimulation (3 Hz, 2 min). The prejunctional apparent affinities were compared with those obtained for postjunctional muscarine receptors mediating the methacholine-induced contraction of the isolated rabbit iris sphincter muscle. Prejunctional apparent affinity constants of pirenzepine (6.67), himbacine (8.51), methoctramine (7.92), 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP, 8.00), hexahydro-d…

Muscarinic Properties of Compounds Related to Arecaidine Propargyl Ester

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 (M 3 receptor subtype) and guinea-pig left atria (M 2 receptor subtype) as well as on rabbit isolated vas deferens (M 1 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 selectivit…

Characterization of the prejunctional muscarinic receptors mediating inhibition of evoked release of endogenous noradrenaline in rabbit isolated vas deferens

The aim of the present study was to characterize the prejunctional modulation of evoked release of endogenous noradrenaline in rabbit vas deferens by the use of muscarinic receptor agonists and subtype-preferring antagonists. Vasa deferentia of the rabbit were stimulated electrically by trains of 120 pulses delivered at 4 Hz or trains of 30 pulses at 1 Hz. The inhibition by muscarinic agonists of the stimulation-evoked overflow of endogenous noradrenaline in the absence and presence of antagonists was used to determine affinity constants for antagonists. These values were compared with those observed at putative M1 receptors inhibiting neurogenic twitch contractions in the rabbit vas defere…

ChemInform Abstract: Regioisomeric 5(3)-Aminomethyl-3(5)-phenylisoxazoles: Synthesis, Spectroscopic Discrimination, and Muscarinic Activity.

The regioselective synthesis of isomeric 5(3)-aminomethyl-3(5)-phenyl isoxazoles using different methods is described. Spectroscopic data, especially mass spectrometric fragmentation, were used to identify and characterize the regioisomers. The muscarinic activity of these isoxazoles was assayed on isolated guinea-pig ileum and atria as well as on isolated rabbit vas deferens. Regioisomere 5(3)-Aminomethyl-3(5)-phenyl-isoxazole: Synthese, spektroskopische Unterscheidung und muskarinische Aktivitat Es werden verschiedene Verfahren zur regioselektiven Darstellung von 5(3)-Aminomethyl-3(5)-phenyl-isoxazolen beschrieben, die anhand ihrer spektroskopischen Daten, insbesondere der massenspektrosk…

Synthesis and Muscarinic Activity of Isoxazole-substituted 1,2,5,6-Tetrahydropyridines

ChemInform Abstract: Synthesis and Muscarinic Activity of Isoxazole-Substituted 1,2,5,6- Tetrahydropyridines.

Acetylcholine receptors (muscarinic) in GtoPdb v.2021.3

Muscarinic acetylcholine receptors (mAChRs) (nomenclature as agreed by the NC-IUPHAR Subcommittee on Muscarinic Acetylcholine Receptors [50]) are activated by the endogenous agonist acetylcholine. All five (M1-M5) mAChRs are ubiquitously expressed in the human body and are therefore attractive targets for many disorders. Functionally, M1, M3, and M5 mAChRs preferentially couple to Gq/11 proteins, whilst M2 and M4 mAChRs predominantly couple to Gi/o proteins. Both agonists and antagonists of mAChRs are clinically approved drugs, including pilocarpine for the treatment of elevated intra-ocular pressure and glaucoma, and atropine for the treatment of bradycardia and poisoning by muscarinic age…

Acetylcholine receptors (muscarinic) in GtoPdb v.2021.2

Muscarinic acetylcholine receptors (mAChRs) (nomenclature as agreed by the NC-IUPHAR Subcommittee on Muscarinic Acetylcholine Receptors [50]) are activated by the endogenous agonist acetylcholine. All five (M1-M5) mAChRs are ubiquitously expressed in the human body and are therefore attractive targets for many disorders. Functionally, M1, M3, and M5 mAChRs preferentially couple to Gq/11 proteins, whilst M2 and M4 mAChRs predominantly couple to Gi/o proteins. Both agonists and antagonists of mAChRs are clinically approved drugs, including pilocarpine for the treatment of elevated intra-ocular pressure and glaucoma, and atropine for the treatment of bradycardia and poisoning by muscarinic age…

Regioisomeric 5(3)-aminomethyl-3(5)-phenylisoxazoles: synthesis, spectroscopic discrimination, and muscarinic activity.

The regioselective synthesis of isomeric 5(3)-aminomethyl-3(5)-phenyl isoxazoles using different methods is described. Spectroscopic data, especially mass spectrometric fragmentation, were used to identify and characterize the regioisomers. The muscarinic activity of these isoxazoles was assayed on isolated guinea-pig ileum and atria as well as on isolated rabbit vas deferens. Regioisomere 5(3)-Aminomethyl-3(5)-phenyl-isoxazole: Synthese, spektroskopische Unterscheidung und muskarinische Aktivitat Es werden verschiedene Verfahren zur regioselektiven Darstellung von 5(3)-Aminomethyl-3(5)-phenyl-isoxazolen beschrieben, die anhand ihrer spektroskopischen Daten, insbesondere der massenspektrosk…

Design and pharmacology of quinuclidine derivatives as M2-selective muscarinic receptor ligands

In our search for M2-selective muscarinic receptor antagonists, we synthesized 1,3-disubstituted indenes. The effects of different basic moieties with regard to binding and selectivity towards the five distinct muscarinic receptor subtypes were investigated. The results show that the quinuclidine series afforded the most promising compounds in terms of both receptor affinity and M2-subtype selectivity.

Acetylcholine receptors (muscarinic) (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Muscarinic acetylcholine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Muscarinic Acetylcholine Receptors [45]) are GPCRs of the Class A, rhodopsin-like family where the endogenous agonist is acetylcholine. In addition to the agents listed in the table, AC-42, its structural analogues AC-260584 and 77-LH-28-1, N-desmethylclozapine, TBPB and LuAE51090 have been described as functionally selective agonists of the M1 receptor subtype via binding in a mode distinct from that utilized by non-selective agonists [243, 242, 253, 155, 154, 181, 137, 11, 230]. There are two pharmacologically characterised allosteric sites on muscarinic receptors, one defined by it binding gallami…

The effects of racemic bethanechol and its (R)- and (S)-enantiomers on pre- and postjunctional muscarine receptors in the guinea-pig ileum

The effect of racemic bethanechol and its (R)- and (S)-enantiomers on smooth muscle contraction and outflow of [3H]-acetylcholine were studied in the guinea-pig myenteric plexus-longitudinal muscle preparation that had been preincubated with [3H]-choline. (S)-, racemic, and (R)-bethanechol caused concentration-dependent contractions of the longitudinal muscle. The potency ratio of the strong isomer (S) to the weak one (R) was 915. Racemic and (S)-bethanechol concentration-dependently inhibited the evoked outflow of [3H]-acetylcholine. Racemic bethanechol was more potent than (S)-bethanechol. (R)-bethanechol up to a concentration of 1 mM did no affect the evoked outflow of [3H]-acetylcholine…

Structure-activity relationships of dimethindene derivatives as new M2-selective muscarinic receptor antagonists.

A series of 2,3-disubstituted indenes, which are analogues of the widely used histamine H(1) receptor antagonist dimethindene, have been synthesized and studied as muscarinic and histamine receptor antagonists. The affinities of these compounds for the five human muscarinic receptor subtypes (M(1)-M(5)) and for human histamine H(1) receptors were determined in radioligand binding studies using membranes from transfected Chinese hamster ovary (CHO) cells and [(3)H]N-methylscopolamine ([(3)H]NMS). The results demonstrate that the diisopropyl analogue 19 has a similar high affinity as (S)-dimethindene at M(2) receptors ((S)-dimethindene: pK(i) = 7.52; (-)-19: pK(i) = 7.37) with an improved sel…