Muscarinic receptor differentiation

Mitchelson, F.

doi:10.1016/0163-7258(88)90005-8

Cited by 149 publications

(36 citation statements)

References 271 publications

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“…bladder (Monferini et al 1988) and trachea (Roffel et al 1989) have both M 2 and M 3 receptors. Functionally, however, smooth muscle contraction appears to be mediated through M 3 receptors only (Mitchelson 1988). In cantrast to these reports, Eglen et al (1989) suggested that the muscarinic receptor mediating smooth muscle contraction of the guinea-pig uterus is of the M 2 type.…”

Section: Discussionmentioning

confidence: 98%

“…Radioligand binding as well as in vitro andin vivo functional studies have revealed the existence of at least three pharmacologically distinct musearlnie receptor subtypes, which have been termed Mb M 2 and M 3 (Doods et al 1987;Mitchelson 1988;Levine and Birdsall 1989). M 1 receptors are mainly present in neuronal tissues (e. g. autonomic ganglia, cerebral cortex and hippocampus) and are characterized by a high affinity for pirenzepine (affinity profile M 1 > M 3 ;?…”

Section: Introductionmentioning

confidence: 99%

“…As smooth muscle contraction is usually mediated by M 3 receptors (Mitchelson 1988), we have reevaluated this finding using a larger nurober of selective antagonists. The affinity values obtained in uteri from immature guinea-pigs were compared to those obtained at M 1 receptors in rabbit vas deferens, M 2 re~ ceptors in guinea-pig atria and smooth muscle M 3 recep~ tors in guinea-pig ileum.…”

Section: Introductionmentioning

confidence: 99%

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Novel pharmacological profile of muscarinic receptors mediating contraction of the guinea-pig uterus

Dörje

Friebe

Tacke

et al. 1990

Naunyn-Schmiedeberg's Arch Pharmacol

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Summary. The present study was designed to further characterize the muscarinic receptors mediating contraction of the guinea-pig uterus. The affinities of various selective muscarinic antagonists were determined and compared with those obtained at M 1 (rabbit vas deferens), M 2 (guinea-pig atria) and M 3 receptors (guinea-pig ileum).The contractile responses of uterine smooth muscle from immature guinea-pigs to carbachol (pD 2 = 5.73)were competitively antagonized by pirenzepine (pA 2 = 7.04), AF-DX 116diazepin-6-one) (pA 2 = 6.96), himbacine (pA 2 = 7.92), methoctramine (pA 2 = 7.52), 4-DAMP (4-diphenylacetoxy-N-methylpiperidine methiodide) (pA 2 = 8.87) and sila-hexocyclium (pA 2 = 8.81). A comparison of affinity values indicates that the muscarinic receptors present in guinea-pig uterus display a novel pharmacological profile which is not consistent with the presence of either an M 1 , M 2 or M 3 receptor. The affinities determined for the different antagonists rather showed a close similarity to those obtained at muscarinic receptors present in rat striatum and NG108-15 cells which are considered pharmacological equivalents (M 4 receptors) of the m4 gene product. We thus hypothesize that the guinea-pig isolated uterus preparation may serve as a simple functional assay system to study the pharmacology of M 4 receptors.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel pharmacological profile of muscarinic receptors mediating contraction of the guinea-pig uterus

Dörje

Friebe

Tacke

et al. 1990

Naunyn-Schmiedeberg's Arch Pharmacol

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“…The subtypes have been termed M 1 (neuronal type), M 2 (M 2 a; cardiac type) and M 3 (M 2 p smooth musclejglandular type) receptors (for recent reviews see Mitchelson, 1988;Melchiorre, 1988;Mutschier et al, 1988). Five receptor subtypes were identified by molecular cloning studies and were found to be the products of distinct genes.…”

Section: Introductionmentioning

confidence: 99%

Muscarinic receptor subtypes in rat pancreatic islets: binding and functional studies

Verspohl

Tacke

Mutschler

et al. 1990

European Journal of Pharmacology

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Cholinergie agents arepotent modulators of insulin release that aet via musearinie reeeptors. We now investigated the musearlnie receptor subtype present in rat panereatic islets in binding and funetional studies. Binding of 5 nM [ 3 H]N-methylscopolamine ([ 3 H]NMS) was half maximal at 30 min. At 60 min, the maximal total bindingwas 1.29% and the non-specifie binding (presence of 100 ,uM atropine) was 0.18% of the total radioaetivity per 10 f.'g islet protein. The high-affinity Kds were 8.5, 56, 1300 and 1300 nM, respectively. The high affinity Kd of the muscarinie receptor agonist, arecaidine propargyl ester (APE), was 8.1 nM. The EC 50 for the biologieal effects of APE on insulin and glucagon secretion was 3.2 and 2.3 nM. The rank order for the high-affinity biological effects of antagonists (inhibition of APE-mediated insulin/ glucagon release) was almost the same as for binding. The data indicate that rat pancreatie islets contain neither an MI subtype (high-affinity for pirenzepine) nor an M 2 subtype (high-affinity for methoctramine) receptor. However, the data evidence an M 3 receptor subtype, since SiHC in the absence of the M 1 receptor subtype shows a relatively high affinity to the receptors in rat panereatie islets.

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Waelbroeck¹,

Camus²,

Tastenoy³

et al. 1991

Chirality

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ABSTRACT(R)-Hexahydro-difenidol has a higher affinity for M 1 receptors in NB-OK 1 cells, pancreas M 3 and striatum M 4 receptors (pKi 7.9 to 8.3) than for cardiac M 2 receptors (pKi 7 .0). (8)-Hexahydro-difenidol, by contrast, is nonselective (pKi 5.8 to 6.1). Our goal in the present study was to evaluate the importance ofthe hydrophobic phenyl, and cyclohexyl rings of hexahydro-difenidol for the stereoselectivity and reeeptor selectivity of hexahydro-difenidol binding to the four muscarinic receptors. Our results indieated that replacement of the phenyl ring of hexahydro-difenidol by a cyclohexyl group <~ dicyclidol) and ofthe cyclohexyl ring by a phenyl moiety <~ difenidol) indueed a !arge (4-to 80-fold) decrease in binding affinity for all musearlnie receptors. Difenidol had a signifieant preference for M 1 , M 3 , and M 4 over M 2 receptors; dicyclidol, by eontrast, had a greater affinity for M 1 and M 4 than for M 2 and M 3 receptors. The binding free energy deerease due to replacement ofthe phenyl and the cyelohexyl groups of(R)-hexahydro-difenidol by, respectively, a eyclohexyl and a phenyl moiety was almostadditive in the ease of M 4 (striatum) binding sites. In the ease ofthe cardiac M 2 , pancreatic M 3 , or NB-OK 1 M 1 receptors the respective binding free energies were not eompletely additive. These results suggest that the four (R)-hexahydro-difenidol ''binding moieties" (phenyl, cyclohexyl, hydroxy, and protonated amino group) cannot simultaneously form optimal interaetions with the M 1 , M 2 , and M 3 muscarinic receptors. When eaeh of the hydrophobic groups is modified, the position of the whole molecule, relative to the four subsites, was changed to allow an optimal overall interaction with the musearlnie receptor.

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Muscarinic receptor differentiation

Cited by 149 publications

References 271 publications

Novel pharmacological profile of muscarinic receptors mediating contraction of the guinea-pig uterus

Novel pharmacological profile of muscarinic receptors mediating contraction of the guinea-pig uterus

Muscarinic receptor subtypes in rat pancreatic islets: binding and functional studies

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

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Muscarinic receptor differentiation

Cited by 149 publications

References 271 publications

Novel pharmacological profile of muscarinic receptors mediating contraction of the guinea-pig uterus

Novel pharmacological profile of muscarinic receptors mediating contraction of the guinea-pig uterus

Muscarinic receptor subtypes in rat pancreatic islets: binding and functional studies

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

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