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L‐689,660, a novel cholinomimetic with functional selectivity for M 1 and M 3 muscarinic receptors

1992; Wiley; Volume: 107; Issue: 2 Linguagem: Inglês

10.1111/j.1476-5381.1992.tb12773.x

1476-5381

Richard Hargreaves, A.T. McKnight, Kate Scholey, Nigel R. Newberry, Leslie J. Street, Peter H. Hutson, J.E. Semark, Elizabeth A. Harley, Sushma Patel, Stephen B. Freedman,

Ion channel regulation and function

L‐689,660, 1‐azabicyclo[2.2.2]octane, 3‐(6‐chloropyrazinyl)maleate, a novel cholinomimetic, demonstrated high affinity binding (p K D (apparent) 7.42) at rat cerebral cortex muscarinic receptors. L‐689,660 had a low ratio (34) of p K D (apparent) values for the displacement of binding of the antagonist [ 3 H]‐N‐methylscopolamine ([ 3 H]‐NMS) compared with the displacement of the agonist [ 3 H]‐oxotremorine‐M ([ 3 H]‐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. L‐689,660 showed no muscarinic receptor subtype selectivity in radioligand binding assays but showed functional selectivity in pharmacological assays. At M 1 muscarinic receptors in the rat superior cervical ganglion, L‐689,660 was a potent (pEC 50 7.3 ± 0.2) full agonist in comparison with (±)‐muscarine. At M 3 receptors in the guinea‐pig ileum myenteric plexus‐longitudinal muscle or in trachea, L‐689,660 was again a potent agonist (pEC 50 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 M 2 receptors in guinea‐pig atria (pA 2 7.2 (95% confidence limits 7, 7.4)) and at muscarinic autoreceptors in rat hippocampal slices. The putative M 1 ‐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‐dione hydrochloride) 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 M 1 , M 2 and M 3 receptors in the functional pharmacological assays. 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.