Synthesis and muscarinic receptor pharmacology of a series of 4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridine bioisosteres of arecoline
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Synthesis and muscarinic receptor pharmacology of a series of 4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridine bioisosteres of arecoline. / Pedersen, H; Bräuner-Osborne, H; Ball, R G; Frydenvang, Karla Andrea; Meier, E; Bøgesø, K P; Krogsgaard-Larsen, P.
In: Bioorganic & Medicinal Chemistry, Vol. 7, No. 5, 1999, p. 795-809.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Synthesis and muscarinic receptor pharmacology of a series of 4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridine bioisosteres of arecoline
AU - Pedersen, H
AU - Bräuner-Osborne, H
AU - Ball, R G
AU - Frydenvang, Karla Andrea
AU - Meier, E
AU - Bøgesø, K P
AU - Krogsgaard-Larsen, P
PY - 1999
Y1 - 1999
N2 - A series of O- and ring-alkylated derivatives of 4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridin-3-ol was synthesized via treatment of appropriately substituted 4-benzylamino-1,2,5,6-tetrahydropyridine-3-carboxamides with hydrogen sulfide and subsequent ring closure by oxidation with bromine. The muscarinic receptor affinity as well as estimated relative efficacy and subtype selectivity of this series of bicyclic arecoline bioisosteres were determined using rat brain membranes and a number of tritiated muscarinic receptor ligands. The effects at the five cloned human muscarinic receptor subtypes of a selected series of chiral analogues, with established absolute stereochemistry, were studied using receptor selection and amplification technology (R-SAT). The potency, relative efficacy, and receptor subtype selectivity of these compounds were related to the structure of the O-substituents and the position and stereochemical orientation of the piperidine ring methyl substituents.
AB - A series of O- and ring-alkylated derivatives of 4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridin-3-ol was synthesized via treatment of appropriately substituted 4-benzylamino-1,2,5,6-tetrahydropyridine-3-carboxamides with hydrogen sulfide and subsequent ring closure by oxidation with bromine. The muscarinic receptor affinity as well as estimated relative efficacy and subtype selectivity of this series of bicyclic arecoline bioisosteres were determined using rat brain membranes and a number of tritiated muscarinic receptor ligands. The effects at the five cloned human muscarinic receptor subtypes of a selected series of chiral analogues, with established absolute stereochemistry, were studied using receptor selection and amplification technology (R-SAT). The potency, relative efficacy, and receptor subtype selectivity of these compounds were related to the structure of the O-substituents and the position and stereochemical orientation of the piperidine ring methyl substituents.
KW - Animals
KW - Arecoline
KW - Brain
KW - Carbachol
KW - Crystallography, X-Ray
KW - Dose-Response Relationship, Drug
KW - Humans
KW - Models, Chemical
KW - Models, Molecular
KW - Myocardium
KW - Pyridines
KW - Rats
KW - Receptors, Muscarinic
M3 - Journal article
C2 - 10400332
VL - 7
SP - 795
EP - 809
JO - Bioorganic & Medicinal Chemistry
JF - Bioorganic & Medicinal Chemistry
SN - 0968-0896
IS - 5
ER -
ID: 40372372