Muscarinic Acetylcholine Receptor Interactions
Published by Anonymous on 2007/9/30 (4422 reads)
1: Life Sci. 1993;53(19):1447-63.
Mutational analysis of muscarinic acetylcholine receptors: structural basis of ligand/receptor/G protein interactions.
Wess J.
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
Molecular cloning studies have revealed the existence of five molecularly distinct muscarinic acetylcholine receptors (m1-m5), which differ in their tissue distribution, ligand binding properties, and functional profiles. Structurally (and functionally), the muscarinic receptors are members of the superfamily of G protein-coupled receptors. A variety of different mutagenesis techniques have been used to study the molecular basis of muscarinic receptor function. This approach has led to the identification of distinct receptor domains (or individual amino acids) predicted to play key roles in ligand binding, agonist-dependent receptor activation, and G protein coupling. Since all G protein-linked receptors share a similar molecular architecture, the information gained from the mutational analysis of muscarinic receptors should help delineate functionally important regions of other members of this receptor family.
Publication Types:
Review
PMID: 8412508 [PubMed - indexed for MEDLINE]
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2: Drug Des Discov. 1993;9(3-4):237-50.
Conformational aspects of the muscarinic receptor interactions of bicyclic isoxazole ester bioisosteres of arecoline.
Lagersted A, Falch E, Ebert B, Krogsgaard-Larsen P.
Department of Organic Chemistry, Royal Danish School of Pharmacy, Copenhagen.
3-Methoxy-4,5,6,7-tetrahydroisoxazolo [4,5-c]pyridine (O-Me-THPO) and O,5-di-Me-THPO are conformationally restricted bioisosteres of the muscarinic agonists norarecoline and arecoline, respectively, showing partial agonist effects at muscarinic acetylcholine receptors. The 7-membered ring analogue of O-Me-THPO, 3-methoxy-5,6,7,8-tetrahydro-4H-isoxazolo[4,5-c]azepine (O-Me-THAO), shows higher affinity for muscarinic receptor sites than O-Me-THPO or O,5-di-Me-THPO. Similarly, O-Et-THAO binds much more tightly to muscarinic receptor sites than its 6-membered ring analogues, O-Et-THPO and O-Et-5-Me-THPO. Based on receptor binding data, O-Me-THPO and O-Me-THAO, and O-Et-THPO and O-Et-THAO, respectively, show similar degrees of partial agonism. They also show similar relative affinities for muscarinic M1 and M2 receptor sites. Using the semiempirical quantum mechanics programme, AM1, and the molecular mechanics programme, SYBYL, we have studied the conformational flexibility of the O-alkyl-THPO and O-alkyl-THAO ring systems. As expected, the 7-membered ring of the latter system was shown to be markedly more flexible than the piperidine rings of O-alkyl-THPO analogues. On the basis of this analysis, a common pharmacophore for these two classes of compounds was constructed.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 8400005 [PubMed - indexed for MEDLINE]
Mutational analysis of muscarinic acetylcholine receptors: structural basis of ligand/receptor/G protein interactions.
Wess J.
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
Molecular cloning studies have revealed the existence of five molecularly distinct muscarinic acetylcholine receptors (m1-m5), which differ in their tissue distribution, ligand binding properties, and functional profiles. Structurally (and functionally), the muscarinic receptors are members of the superfamily of G protein-coupled receptors. A variety of different mutagenesis techniques have been used to study the molecular basis of muscarinic receptor function. This approach has led to the identification of distinct receptor domains (or individual amino acids) predicted to play key roles in ligand binding, agonist-dependent receptor activation, and G protein coupling. Since all G protein-linked receptors share a similar molecular architecture, the information gained from the mutational analysis of muscarinic receptors should help delineate functionally important regions of other members of this receptor family.
Publication Types:
Review
PMID: 8412508 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
2: Drug Des Discov. 1993;9(3-4):237-50.
Conformational aspects of the muscarinic receptor interactions of bicyclic isoxazole ester bioisosteres of arecoline.
Lagersted A, Falch E, Ebert B, Krogsgaard-Larsen P.
Department of Organic Chemistry, Royal Danish School of Pharmacy, Copenhagen.
3-Methoxy-4,5,6,7-tetrahydroisoxazolo [4,5-c]pyridine (O-Me-THPO) and O,5-di-Me-THPO are conformationally restricted bioisosteres of the muscarinic agonists norarecoline and arecoline, respectively, showing partial agonist effects at muscarinic acetylcholine receptors. The 7-membered ring analogue of O-Me-THPO, 3-methoxy-5,6,7,8-tetrahydro-4H-isoxazolo[4,5-c]azepine (O-Me-THAO), shows higher affinity for muscarinic receptor sites than O-Me-THPO or O,5-di-Me-THPO. Similarly, O-Et-THAO binds much more tightly to muscarinic receptor sites than its 6-membered ring analogues, O-Et-THPO and O-Et-5-Me-THPO. Based on receptor binding data, O-Me-THPO and O-Me-THAO, and O-Et-THPO and O-Et-THAO, respectively, show similar degrees of partial agonism. They also show similar relative affinities for muscarinic M1 and M2 receptor sites. Using the semiempirical quantum mechanics programme, AM1, and the molecular mechanics programme, SYBYL, we have studied the conformational flexibility of the O-alkyl-THPO and O-alkyl-THAO ring systems. As expected, the 7-membered ring of the latter system was shown to be markedly more flexible than the piperidine rings of O-alkyl-THPO analogues. On the basis of this analysis, a common pharmacophore for these two classes of compounds was constructed.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 8400005 [PubMed - indexed for MEDLINE]
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Muscarinic Acetylcholine Receptor Function
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Muscarinic Acetylcholine Receptor Expression
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