Binding profile of a novel cardioselective muscarine receptor antagonist, AF-DX 116, to membranes of peripheral tissues and brain in the rat

Hammer, Rudolf; Giraldo, E.; Schiavi, G.B.; Monferini, E.; Ladinsky, H.

doi:10.1016/0024-3205(86)90409-1

Cited by 366 publications

(138 citation statements)

References 7 publications

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“…M 2 and M 3 receptors are primarily found in lower brain areas and in peripheral effector argans such as heart (M 2 ), smooth muscle (M 3 ) and glands (M 3 ) and display low affinity for pirenzepine. They can be distinguished by the use of selective antagonists such as methoctramine and AF-DX 116 (M 2 > M 1 > M 3 ) (Melchiorre et al 1987;Hammer et al 1986;Micheletti et al 1987), himbacine (M 1 ~ M 2 > M 3 ) (Gilani and Cobbin 1986;Lazareno and Roberts 1989), sila-hexocyclium (M 1 ~ M 3 > M 2 ) Waelbroeck et al 1989), 4-DAMP and hexahydro-sila-difenidol (M 3 ::? :: M 1 > M 2 ) (Barlow et al 1976;Mutschier and Lambrecht 1984;.…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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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“…Moreover, different sensitivities to pertussis toxin of the cellular responses mediated by individual mAChR subtypes suggest that the response induced by mAChR I or mAChR III and that induced by mAChR II or mAChR IV occur through distinct G-proteins [5,10,11]. The antagonist binding properties of individual mAChR subtypes expressed in Xenopus oocytes [2,3,12] show that mAChR I, mAChR II and mAChR III correspond most closely to the pharmacologically defined M1 (I), M2 cardiac (II) and M2 glandular (III) subtypes [13][14][15], respectively. This, together with the differential tissue distribution of the mRNAs encoding the individual mAChR species [2,[16][17][18][19], indicates that the mAChR heterogeneity in tissues with respect to antagonist binding is attributable to the presence of distinct mAChR gene products by themselves or in various combinations.…”

Section: Introductionmentioning

confidence: 99%

Location of a region of the muscarinic acetylcholine receptor involved in selective effector coupling

et al. 1988

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Chimaeric muscarinic acetylcholine receptors (mAChR) in which corresponding portions of mAChR I and mAChR II are replaced with each other have been produced in Jfenopus oocytes by expression of cDNA constructs encoding them.Functional analysis of the chimaeric mAChRs indicates that a region mostly comprising the putative cytoplasmic portion between the proposed transmembrane segments V and VI is involved in selective coupling of mAChR I and mAChR II with different effector systems. In contrast, the exchange of this region between mAChR I and mAChR II does not significantly affect the antagonist binding properties of the two mAChR subtypes.

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“…4 -6 M 2 receptors, with a low affinity for pirenzepine and a high affinity for AF-DX 116, are typical of eardiac tissues. 7 They show a .low affini ty for 4-DAMP and hexahydro-sll adifenidol. "-6·8·9 M 3 receptors have low affinities for pirenzepine and AF-DX 116, and high affinities for 4-DAMP10 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

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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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Binding profile of a novel cardioselective muscarine receptor antagonist, AF-DX 116, to membranes of peripheral tissues and brain in the rat

Cited by 366 publications

References 7 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

Location of a region of the muscarinic acetylcholine receptor involved in selective effector coupling

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

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Binding profile of a novel cardioselective muscarine receptor antagonist, AF-DX 116, to membranes of peripheral tissues and brain in the rat

Cited by 366 publications

References 7 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

Location of a region of the muscarinic acetylcholine receptor involved in selective effector coupling

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