The Binding Properties of Muscarinic Receptors

Birdsall, N. J. M.; Hulme, Edward C.

doi:10.1007/978-1-4612-4498-1_2

Cited by 14 publications

(11 citation statements)

References 169 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The binding affinity of muscarinic agonists also can be increased with divalent cations (reviewed in Birdsall and Hulme, 1989) and by the sodium channel activator batrachotoxin (Minton and Sokolovsky, 1990).…”

Section: Discussionmentioning

confidence: 99%

Subtype-Selective Positive Cooperative Interactions between Brucine Analogues and Acetylcholine at Muscarinic Receptors: Radioligand Binding Studies

Lazareno

Gharagozloo²,

Kuonen³

et al. 1998

Molecular Pharmacology

Self Cite

105

View full text Add to dashboard Cite

We studied the interactions of strychnine, brucine, and three of the N-substituted analogues of brucine with [3 H]N-methylscopolamine (NMS) and unlabeled acetylcholine at m1-m5 muscarinic receptors using equilibrium and nonequilibrium radioligand binding studies. The results were consistent with a ternary allosteric model in which both the primary and allosteric ligands bind simultaneously to the receptor and modify the affinities of each other. The compounds had K d values in the submillimolar range, inhibited [ 3 H]NMS dissociation, and showed various patterns of positive, neutral, and negative cooperativity with [ 3 H]NMS and acetylcholine, but there was no predictive relationship between the effects. Acetylcholine affinity was increased ϳ2-fold by brucine at m1 receptors, ϳ3-fold by Nchloromethyl brucine at m3 receptors, and ϳ1.5-fold by brucine-N-oxide at m4 receptors. The existence of neutral cooperativity, in which the compound bound to the receptor but did not modify the affinity of acetylcholine, provides the opportunity for a novel form of drug selectivity that we refer to as absolute subtype selectivity: an agent showing positive or negative cooperativity with the endogenous ligand at one receptor subtype and neutral cooperativity at the other subtypes would exert functional effects at only the one subtype, regardless of the concentration of agent or its affinities for the subtypes. Our results demonstrate the potential for developing allosteric enhancers of acetylcholine affinity at individual subtypes of muscarinic receptor and suggest that minor modification of a compound showing positive, neutral, or low negative cooperativity with acetylcholine may yield compounds with various patterns of cooperativity across the receptor subtypes.

show abstract

Section: Discussionmentioning

confidence: 99%

Subtype-Selective Positive Cooperative Interactions between Brucine Analogues and Acetylcholine at Muscarinic Receptors: Radioligand Binding Studies

Lazareno

Gharagozloo²,

Kuonen³

et al. 1998

Molecular Pharmacology

Self Cite

105

View full text Add to dashboard Cite

show abstract

“…In this cell line the muscarinic receptor is of the M4 sub-type, and agonist stimulation leads to an inhibition of adenylate cyclase (Evans et al, 1984;Peralta et al, 1987). Delivery of muscarinic receptors to the plasma membrane was measured by irreversibly alkylating receptors already at the membrane with propyl-benzilylcholine mustard (PrBCM;Young et al, 1972) and then following the recovery of the binding of [3H]-N-methylscopolamine, a polar, membrane-impermeant radioligand (Birdsall & Hulme, 1989). A preliminary account of this work has been presented to the British Pharmacological Society (Koenig & Edwardson, 1993).…”

Section: Introductionmentioning

confidence: 99%

Routes of delivery of muscarinic acetylcholine receptors to the plasma membrane in NG108‐15 cells

Koenig

Edwardson

1994

British J Pharmacology

View full text Add to dashboard Cite

“…M1 receptors are above all found in the nervous system and are characterized by a high affinity for pirenzepine Birdsall et al, 1980;Brown et al, 1980;Hammer & Giachetti, 1982;Lambrecht et al, 1988b). M2 receptors, which show low affinity for pirenzepine, have been further subdivided into cardiac type and glandular/ smooth muscle subtypes by use of selective antago-1 Author for correspondence.…”

Section: Introductionmentioning

confidence: 99%

Binding and functional properties of antimuscarinics of the hexocyclium/sila‐hexocyclium and hexahydro‐diphenidol/hexahydro‐sila‐diphenidol type to muscarinic receptor subtypes

Waelbroeck

Tastenoy

Camus

et al. 1989

British J Pharmacology

View full text Add to dashboard Cite

In an attempt to assess the structural requirements for the muscarinic receptor selectivity of hexahydro-diphenidol (hexahydro-difenidol) and hexahydro-sila-diphenidol (hexahydro-sila-difenidol), a series of structurally related C/Si pairs were investigated, along with atropine, pirenzepine and methoctramine, for their binding affinities in NB-OK 1 cells as well as in rat heart and pancreas.2 The action of these antagonists at muscarinic receptors mediating negative inotropic responses in guinea-pig atria and ileal contractions has also been assessed. 3 Antagonist binding data indicated that NB-OK 1 cells (M1 type) as well as rat heart (cardiac type) and pancreas (glandular/smooth muscle type) possess different muscarinic receptor subtypes. 4 A highly significant correlation was found between the binding affinities of the antagonists to muscarinic receptors in rat heart and pancreas, respectively, and the affinities to muscarinic receptors in guinea-pig atria and ileum. This implies that the muscarinic binding sites in rat heart and the receptors in guinea-pig atria are essentially similar, but different from those in pancreas and ileum. 5 The antimuscarinic potency of hexahydro-diphenidol and hexahydro-sila-diphenidol at the three subtypes was influenced differently by structural modifications (e.g. quaternization). Different selectivity profiles for the antagonists were obtained, which makes these compounds useful tools to investigate further muscarinic receptor heterogeneity. Indeed, the tertiary analogues hexahydrodiphenidol (HHD) and hexahydro-sila-diphenidol (HHSiD) had an M1 = glandular/smooth muscle > cardiac selectivity profile, whereas the quaternary analogues HHD methiodide and HHSiD methiodide were M1 preferring (M1 > glandular/smooth muscle, cardiac).

show abstract

The Binding Properties of Muscarinic Receptors

Cited by 14 publications

References 169 publications

Subtype-Selective Positive Cooperative Interactions between Brucine Analogues and Acetylcholine at Muscarinic Receptors: Radioligand Binding Studies

Subtype-Selective Positive Cooperative Interactions between Brucine Analogues and Acetylcholine at Muscarinic Receptors: Radioligand Binding Studies

Routes of delivery of muscarinic acetylcholine receptors to the plasma membrane in NG108‐15 cells

Binding and functional properties of antimuscarinics of the hexocyclium/sila‐hexocyclium and hexahydro‐diphenidol/hexahydro‐sila‐diphenidol type to muscarinic receptor subtypes

Contact Info

Product

Resources

About