Muscarinic receptor subtypes - search for selective agonists and antagonists

Mutschler, E.; Ensinger, Helmut A.; Gross, J.; Leis, Albrecht; Mendla, Klaus; Moser, Ulrich; Pfaff, Otmar; Reichel, Dirk; Rühlmann, Klaus; Tacke, Reinhold; Waelbroeck, Magalì; Wehrle, J.; Lambrecht, Günter

doi:10.1016/s0165-7208(96)80007-9

Cited by 3 publications

(2 citation statements)

References 34 publications

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“…During the past decade, several antago nists have been developed which exhibit dis tinct differential affinity of binding to m 1 ver sus m2 muscarinic receptors [25], Investiga tion of the molecular basis of such receptor subtype selectivity through induction of point mutations and creation of receptor chimeras has resulted in elucidation of sequences which might be important for such selectivity [29], Furthermore, it is becoming obvious that multiple receptor domains contribute to a dif ferent extent to the subtype selectivity of var ious antagonists [30]. Our results indicate that the interesting LYTTYL-LYTLYT difference in the primary sequence of the two receptor subtypes is not important for preferential binding of receptor subtype selective antago nists to one receptor subtye versus the other.…”

Section: Discussionmentioning

confidence: 99%

“…A series of these antagonists were used for this purpose, including the ml-selective antago nists pirenzepine and telenzepine and the m2-selective antagonists gallamine, AF-DX 116, methoctramine, himbacine, and AQ-RA 741 [24][25][26]. The affinities of these antagonists for wild-type and mutant muscarinic receptors were estimated by their competition with [3H]NMS in intact CHO cells.…”

Section: Effects O F the L Yttyl L Ytl Yt (M L) And L Ytl Yt -» L Yttmentioning

confidence: 99%

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Investigation of the Role of an Amino Acid Triplet Repeat in Differentiating Drug-Receptor Interaction at ml and m2 Muscarinic Receptors

et al. 1995

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The first putative extracellular domains of both ml and ml muscarinic receptors contain a triplet of amino acid residues consisting of leucine (L), tyrosine (Y), and threonine (T). This triplet is repeated as LYTLYT in m2 receptors. However, it is repeated in a transposed fashion (LYTTYL) in the sequence of ml receptors. In this work we employed site-directed mutagenesis to investigate the possible significance of this unique sequence diversity in determining the distinct differential drug-receptor interaction at the two receptor subtypes. Mutation of the LYTTYL sequence of ml receptors to the corresponding m2 receptor LYTLYT sequence, however, did not significantly change the binding affinity of the agonist carbachol or the affinity of the majority of a series of receptor antagonists which are able to discriminate between wild-type ml and m2 receptors. The reverse mutation at the m2 receptor also did not modify agonist affinity, but altered affinity of several receptor subtype-selective antagonists. The magnitude of affinity changes, however, was small, and the direction of these changes was opposite to what would be expected if the m2 receptor LYTLYT sequence were important for determining the binding profile of m2-receptor-selective antagonists. Our data suggest that the LYTTYL-LYTLYT sequence differences between ml and m2 muscarinic receptors are not important for determining receptor pharmacology.

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Section: Discussionmentioning

confidence: 99%

Section: Effects O F the L Yttyl L Ytl Yt (M L) And L Ytl Yt -» L Yttmentioning

confidence: 99%

Investigation of the Role of an Amino Acid Triplet Repeat in Differentiating Drug-Receptor Interaction at ml and m2 Muscarinic Receptors

et al. 1995

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Neuro- and psychopharmacological investigation of the alkaloids convolvine and atropine

Mirzaev¹,

Aripova²

1998

Chem Nat Compd

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It has been established that convolvine blocks the M-receptors of the heart and intestine but ra&es the sensitivity of the M-receptors of the salivary gland and of the CNS, while atropine blocks all the abovementioned M-receptors. Convolvine has revealed characteristics of a sedative and nootropic agent. Atropine, however, which is known as a psychomotor stimulator, prevents the realization of a conditioned gastromotor reflex. An analysis has been made of the relationship between features of the pharmacological activities and chemical structures of convolvine and atropine.Plants of the genus Convolvulus (bindweed) were first studied by A. P. Orekhov, R. A. Konovalova [1], and S. Yu. Yunusov. From C. pseudocantabrica and C. subhirsutus they isolated the two alkaloids convolvine and convolamine and established their structures. They were the first to show the presence of tropane alkaloids in plants of the Convolvulaceae family. S. Yu. Yunusov and coworkers determined the maximum amounts of the total alkaloids in the epigeal parts of the plants --2.08% --and in the roots --4.1% [2].The main alkaloid of both species is convolvine, making up about 1% of the air-dry weight of the raw material. Convolvine (1) is an ester of the amino alcohol nortropine and 3,4-dimethoxybenzoic (veratric) acid and belongs to the class of tropane alkaloids, like atropine (2), which is an ester of the amino alcohol tropine and dl-tropic acid. Atropine is one of the standard M-cholinoblockers. With the aim of evaluating the neuro-and psychotropic activities of convolvine and also to elucidate the relationship between structural features and biological activity we have made a comparative study of convolvine and atropine in those directions where the pharmacological properties of the latter are generally known.

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