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Muscarinic receptor characterization and evaluation of a series of novel muscarinic ligands in the isolated rabbit thoracic aorta
1004
Abstracts
Vol. 56, No.s 11/12, 199.5
3 SIDECHAIN
STERIC BULK AND MUSCARINIC
AGONIST SAR IN ALKOXY-TZTP’S.
C. H. Mitch, F. P. Bymaster, D. 0. Calligaro, S. J. Quimby, B. D. Sawyer, J. S. Ward, P. H. Olesen, P. Sauerberg, M. J. Sheardown, P. D. Suzdak, M. Swedberg and H. E. Shannon. Lilly Research Laboratories, a Division of Eli Lilly and Co., Lilly Corporate Center, Indianapolis, IN 46285 and Novo Nordisk, CNS Division, Malov, Denmark. The effect of increasing sidechain steric bulk in relation to muscarinic agonist activity was examined in a series of alkoxy substituted TZTP’s (3-thiadiazol-3-yl1,2,5,6_tetrahydro- lmethylpyridines). Steric bulk of the substituent on the end of a propoxy sidechain on the thiadiaozole group was varied through the series isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl and 2-thienyl. Muscarinic agonist activity was evaluated in rabbit vas deferens by inhibition of electrically stimulated muscle contractions. Among the aliphatitc substituents, isopropyl was most potent with an IC50 of 0.006 nM. Increasing steric bulk correspondingly decreased muscarinic agonist potency, with cyclopentyl having an IC50 of 363 nM while cyclohexyl failed to produce a 50% inhibition at doses up to 1OuM. In contrast, the less bulky aromatic substituents retained muscarinic agonist potency with phenyl substitution having an IC50 of 7 nM and thienyl substitution an IC50 of 0.145 nM.
4 MUSCARTNIC RECEPTOR CHARACTERIZATION AND EVALUATION OF A SERIES OF NOVEL MUSCARINIC LIGANDS IN THE ISOLATED RABBIT THORACIC AORTA. B. D. Sawyer, H. E. Shannon, J. S. Ward, C. H. Mitch, M. J. Sheardown,* P. H. Olesen,* P. The Lilly Research Laboratories, Indianapolis, IN, USA and Novo Nordisk Sauerberg*. Pharmaceutical Division, MAlov, Denmark* Muscarinic cholinergic agonists produce endothelium-dependent relaxation in various intact vascular preparations. Conversely, muscarinic receptor activation in vascular preparations Muscarinic receptors mediating these denuded of endothelium only produces contraction. opposite effects were characterized in isolated ring preparations from rabbit thoracic aorta. Tissues were mounted in 10 ml baths, attached to Grass FT.03 force transducers, and maintained at 370 C and pH 7.4 in a modified Krebs’ solution that was constantly bubbled with 95%02/5% CO2. Tissues were precontracted with 100 nM norepinephrine. Cumulative concentration-response curves for acetylcholine (ACh), carbachol (CC) and oxotremorine (0X0) were constructed. In addition, shifts of the carbachol concentration-response curve in the presence of various concentrations of pirenzepine, AFDX-116 and I-DAMP were determined. ECsc’s for ACh, CC and OX0 were 96, 505 and 272 nM, respectively. In addition, the activities of a series of novel muscarinic ligands were evaluated.
Abstracts
Vol. 56, No.s 11/12, 199.5
3 SIDECHAIN
STERIC BULK AND MUSCARINIC
AGONIST SAR IN ALKOXY-TZTP’S.
C. H. Mitch, F. P. Bymaster, D. 0. Calligaro, S. J. Quimby, B. D. Sawyer, J. S. Ward, P. H. Olesen, P. Sauerberg, M. J. Sheardown, P. D. Suzdak, M. Swedberg and H. E. Shannon. Lilly Research Laboratories, a Division of Eli Lilly and Co., Lilly Corporate Center, Indianapolis, IN 46285 and Novo Nordisk, CNS Division, Malov, Denmark. The effect of increasing sidechain steric bulk in relation to muscarinic agonist activity was examined in a series of alkoxy substituted TZTP’s (3-thiadiazol-3-yl1,2,5,6_tetrahydro- lmethylpyridines). Steric bulk of the substituent on the end of a propoxy sidechain on the thiadiaozole group was varied through the series isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl and 2-thienyl. Muscarinic agonist activity was evaluated in rabbit vas deferens by inhibition of electrically stimulated muscle contractions. Among the aliphatitc substituents, isopropyl was most potent with an IC50 of 0.006 nM. Increasing steric bulk correspondingly decreased muscarinic agonist potency, with cyclopentyl having an IC50 of 363 nM while cyclohexyl failed to produce a 50% inhibition at doses up to 1OuM. In contrast, the less bulky aromatic substituents retained muscarinic agonist potency with phenyl substitution having an IC50 of 7 nM and thienyl substitution an IC50 of 0.145 nM.
4 MUSCARTNIC RECEPTOR CHARACTERIZATION AND EVALUATION OF A SERIES OF NOVEL MUSCARINIC LIGANDS IN THE ISOLATED RABBIT THORACIC AORTA. B. D. Sawyer, H. E. Shannon, J. S. Ward, C. H. Mitch, M. J. Sheardown,* P. H. Olesen,* P. The Lilly Research Laboratories, Indianapolis, IN, USA and Novo Nordisk Sauerberg*. Pharmaceutical Division, MAlov, Denmark* Muscarinic cholinergic agonists produce endothelium-dependent relaxation in various intact vascular preparations. Conversely, muscarinic receptor activation in vascular preparations Muscarinic receptors mediating these denuded of endothelium only produces contraction. opposite effects were characterized in isolated ring preparations from rabbit thoracic aorta. Tissues were mounted in 10 ml baths, attached to Grass FT.03 force transducers, and maintained at 370 C and pH 7.4 in a modified Krebs’ solution that was constantly bubbled with 95%02/5% CO2. Tissues were precontracted with 100 nM norepinephrine. Cumulative concentration-response curves for acetylcholine (ACh), carbachol (CC) and oxotremorine (0X0) were constructed. In addition, shifts of the carbachol concentration-response curve in the presence of various concentrations of pirenzepine, AFDX-116 and I-DAMP were determined. ECsc’s for ACh, CC and OX0 were 96, 505 and 272 nM, respectively. In addition, the activities of a series of novel muscarinic ligands were evaluated.