Pirenzepine distinguishes between different subclasses of muscarinic receptors

Abstract

Some antagonists exhibit tissue selectivity in their pharmacological antagonism of muscarinic responses. However, the affinity constants for equilibrium binding of classical antagonists to muscarinic receptors in subcellular preparations have shown only small variations in different peripheral tissues and regions of the brain. The binding curves do not deviate significantly from the simple Langmuir isotherm, indicating apparent homogeneity of the receptor population in any given region. In contrast, heterogeneity has been detected by agonist binding studies but this may arise from different environmental or coupling restraints on the agonist-induced conformational change and cannot be taken as evidence for different receptor subtypes. We report here binding studies using a new anti-muscarinic drug, pirenzepine, in which we found heterogeneity of binding that correlates well with the pharmacological activity.

Presynaptic M1 muscarinic cholinoceptors mediate inhibition of excitatory synaptic transmission in the hippocampus in vitro

“…The muscarinic receptor antagonist, pirenzepine, competitively antagonized the effects of CCh on the field EPSP with a pA2 of 7.4. These results confirm earlier reports of a presynaptic inhibitory action of CCh in the hippocampal CAI region and provide strong evidence that this effect is mediated by muscarinic receptors of the Mt subtype.The classification of muscarinic receptors into two broad categories on the basis of their high (M0 and low (M2) affinities for the antagonist, pirenzepine [9], has prompted a number of attempts to establish the subtypes mediating the electrophysiological responses to muscarinic agonists throughout the brain [4-6, 14-16, 19]. In hippocampal CA I pyramidal neurones, both the membrane depolarization and blockade of IAHp induced by carbachol (CCh) have been attributed to an action at M1 receptors, whereas inhibition of the M-current may result from M2 receptor activation [4].…”

“…The classification of muscarinic receptors into two broad categories on the basis of their high (M0 and low (M2) affinities for the antagonist, pirenzepine [9], has prompted a number of attempts to establish the subtypes mediating the electrophysiological responses to muscarinic agonists throughout the brain [4-6, 14-16, 19]. In hippocampal CA I pyramidal neurones, both the membrane depolarization and blockade of IAHp induced by carbachol (CCh) have been attributed to an action at M1 receptors, whereas inhibition of the M-current may result from M2 receptor activation [4].…”

Stereoselectivity of (R)‐ and (S)‐hexahydro‐difenidol binding to neuroblastoma M1, cardiac M2, pancreatic M3, and striatum M4 muscarinic receptors

“…The incubation period was 2 h in the presence of 0.25 nM [ 3 H]NMS in order to allow binding equilibrium. This [ 3 H]NMS concentration was equivalent to 2-fold the tracer's K 0 value at M 1 receptors.…”

“…1 • 2 M 1 receptors, with a high affinity for pirenzepine, are typically found in neuronal tissues. 3 These receptors have a low affinity for AF-DX 116 (11-( { (2-[ ( diethy lamino )methy l]-1-pi peridiny I }acety D-5-11-dihydro-6H-pyrido(2,3-b)(1,4)benzodiazepin-6-one) and a high affinity for 4-DAMP (4-diphenylacetoxy-N-methylpiperidine methiodide) and hexahydro-sila-difenidol. 4 -6 M 2 receptors, with a low affinity for pirenzepine and a high affinity for AF-DX 116, are typical of eardiac tissues.…”

“…13 Hexahydro-difenidol ( Fig. 1) is weil characterized as ileum-preferring musearlnie antagonist (high affinity for M 3 greater affinity than M 2 receptors. 5 • 6 • 9 Wehave already demonstrated that muscarinic receptors are capable of discriminating the two enantiomers of hexahydrodifenidol, and have a greater affinity for the (R)-enantiomer.…”