L-689,660, a novel cholinomimetic with functional selectivity for M1 and M3 muscarinic receptors
| Autor: | Kate Scholey, J.E. Semark, A.T. McKnight, Shil Patel, E.A. Harley, Nigel R. Newberry, Peter H. Hutson, Richard Hargreaves, Leslie J. Street, Stephen B. Freedman |
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| Rok vydání: | 1992 |
| Předmět: |
Agonist
Male medicine.medical_specialty Quinuclidines medicine.drug_class Succinimides Thiophenes Pharmacology Muscarinic agonist Partial agonist Rats Sprague-Dawley Bridged Bicyclo Compounds Radioligand Assay Internal medicine Muscarinic acetylcholine receptor Muscarinic acetylcholine receptor M4 medicine Animals Cerebral Cortex Binding Sites Ganglia Sympathetic Chemistry Myocardium Lacrimal Apparatus Muscarinic acetylcholine receptor M3 Muscarinic acetylcholine receptor M2 Muscarinic acetylcholine receptor M1 Bridged Bicyclo Compounds Heterocyclic Receptors Muscarinic Rats Endocrinology Parasympathomimetics Pyrazines Research Article |
| Zdroj: | British journal of pharmacology. 107(2) |
| ISSN: | 0007-1188 |
| Popis: | 1. L-689,660, 1-azabicyclo[2.2.2]octane, 3-(6-chloropyrazinyl)maleate, a novel cholinomimetic, demonstrated high affinity binding (pKD (apparent) 7.42) at rat cerebral cortex muscarinic receptors. L-689,660 had a low ratio (34) of pKD (apparent) values for the displacement of binding of the antagonist ([3H]-N-methylscopolamine ([3H]-NMS) compared with the displacement of the agonist [3H]-oxotremorine-M ([3H]-Oxo-M), in rat cerebral cortex. Low NMS/Oxo-M ratios have been shown previously to be a characteristic of compounds that are low efficacy partial agonists with respect to stimulation of phosphatidyl inositol turnover in the cerebral cortex. 2. L-689,660 showed no muscarinic receptor subtype selectivity in radioligand binding assays but showed functional selectivity in pharmacological assays. At M1 muscarinic receptors in the rat superior cervical ganglion, L-689,660 was a potent (pEC50 7.3 +/- 0.2) full agonist in comparison with (+/-)-muscarine. At M3 receptors in the guinea-pig ileum myenteric plexus-longitudinal muscle or in trachea, L-689,660 was again a potent agonist (pEC50 7.5 +/- 0.2 and 7.7 +/- 0.3 respectively) but had a lower maximum response than carbachol. In contrast L-689,660 was an antagonist at M2 receptors in guinea-pig atria (pA2 7.2 (95% confidence limits 7, 7.4)) and at muscarinic autoreceptors in rat hippocampal slices. 3. The putative M1-selective muscarinic agonist, AF102B (cis-2-methylspiro-(1,3-oxathiolane 5,3')-quinuclidine hydrochloride) was found to have a profile similar to L-689,660 but had up to 100 times less affinity in binding and functional assays.RS-86 (2-ethyl-8-methyl-2,8-diazospiro[4,5]decan 1,3-dionehydrochloride) also had lower affinity than L-689,660, and had no binding selectivity for muscarinic receptor subtypes. RS-86 had a higher NMS/Oxo-M ratio than L-689,660 and was a full agonist at MI,M2 and M3 receptors in the functional pharmacological assays.4. The functional selectivity of L-689,660 in muscarinic pharmacological assays is consistent with the effects of a low efficacy partial agonist in tissues with different effective receptor reserves. |
| Databáze: | OpenAIRE |
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