Four experiments compared the CNS effects of a novel M1/M3 receptor agonist L-689,660 with those of the M1/M3 muscarinic receptor agonist AF102B. In the mouse tail-flick test of antinociception (TF) the minimum effective doses to increase tail-flick latency (MED) of L-689,660 and AF102B were 0.03 mg/kg and 10.0 mg/kg, respectively. In a rat conditioned-suppression-of-drinking (CSD) test of reference memory, doses of 0.3 and 1.0 mg/kg L-689,660 and a dose of 5.0 mg/kg AF102B reversed a scopolamine-induced deficit in performance (0.6 mg/kg). Although there was a tendency for L-689,660 to reverse the scopolamine-induced (0.4 mg/kg) performance deficit in a rat delayed-matching-to-position (DMTP) test, the difference failed to reach statistical significance. In contrast, a 5.0 mg/kg dose of AF102B potentiated the scopolamine-induced deficit in choice accuracy and the number of trials completed on this task. In a response sensitivity (RS) test, chain-pulling rates were significantly decreased by L-689,660 (MED = 0.03 mg/kg) and by AF102B (MED = 5.0 mg/kg). These results suggest that L-689,660 and AF102B may ameliorate or reverse a scopolamine-induced deficit, but only at doses that also reduce chain-pulling rates on operant schedules of reinforcement.

01 Dec 1993·The Journal of Pharmacology and Experimental Therapeutics

Pharmacological characterization of the novel cholinomimetic L-689,660 at cloned and native brain muscarinic receptors.

Author: McKinney, M. ; Aagaard, P.

1-Azabicyclo[2,2,2]octane,3-(6-chloropyrazinyl)maleate (L-689,660) reportedly is an agonist with selectivity for M1 and M3 muscarinic receptors.The authors confirmed this in functional assays of brain muscarinic receptors and of cloned human muscarinic receptors transfected into Chinese hamster ovary (CHO-K1) cells.For stimulation of phosphoinositide turnover in rat cortical and hippocampal dissociated tissue, L-689,660 was a partial agonist (24% and 26% intrinsic activity, resp., relative to oxotremorine-M) with EC₅₀ values of 71 μM and 118 μM, resp.At putative M4 receptors coupled to cAMP inhibition in rat striatum, however, L-689,660 acted as a competitive antagonist (K_B = 0.4 μM).Furthermore, at putative M2/M4 autoreceptors that regulate acetylcholine release in the hippocampus, the drug also behaved as an antagonist (K_B = 2.1 μM).These data indicated that L-689,660 behaves as a postsynaptic agonist/presynaptic antagonist at central cholinergic synapses.Further aspects of the selectivity of the drug for specific muscarinic receptor subtypes were revealed with phosphoinositide turnover assays of cloned muscarinic receptors expressed in CHO-K1 cells.L-689,660 was a partial agonist at transfected hm1 and hm3 receptors and was more potent than oxotremorine-M; however, the drug was inactive at transfected hm5 receptors.Partial agonist activity at hm1 and hm3 muscarinic receptors was present even after using alkylation to reduce receptor numbers to levels comparable to that level found in the hm5 cell line.Thus, with functional assays either with brain tissue or with transfected cell lines, L-689,660 was shown to be an agonist for the M1 and M3 receptors but not for M5 or M4 receptors.Because previous studies have shown that L-689,660 also does not activate M2 receptors, these data taken as a whole reveal a unique pharmacol. profile for this agonist, i.e., it is a drug that activates only M1 and M3 receptors.This in vitro profile suggests that L-689,660 might be a useful cholinomimetic for restoring cholinergic tone at central synapses in the diseased brain.

01 Dec 1993·The Journal of pharmacology and experimental therapeutics

Pharmacological characterization of the novel cholinomimetic L-689,660 at cloned and native brain muscarinic receptors.

Article

Author: McKinney, M ; Aagaard, P

1-Azabicyclo[2,2,2]octane,3-(6-chloropyrazinyl)maleate (L-689,660) reportedly is an agonist with selectivity for M1 and M3 muscarinic receptors. We confirmed this in functional assays of brain muscarinic receptors and of cloned human muscarinic receptors transfected into Chinese hamster ovary (CHO-K1) cells. For stimulation of phosphoinositide turnover in rat cortical and hippocampal dissociated tissue, L-689,660 was a partial agonist (24% and 26% intrinsic activity, respectively, relative to oxotremorine-M) with EC50 values of 71 microM and 118 microM, respectively. At putative M4 receptors coupled to cyclic AMP inhibition in rat striatum, however, L-689,660 acted as a competitive antagonist (KB = 0.4 microM). Furthermore, at putative M2/M4 autoreceptors that regulate acetylcholine release in the hippocampus, the drug also behaved as an antagonist (KB = 2.1 microM). These data indicated that L-689,660 behaves as a postsynaptic agonist/presynaptic antagonist at central cholinergic synapses. Further aspects of the selectivity of the drug for specific muscarinic receptor subtypes were revealed with phosphoinositide turnover assays of cloned muscarinic receptors expressed in CHO-K1 cells. L-689,660 was a partial agonist at transfected hm1 and hm3 receptors and was more potent than oxotremorine-M; however, the drug was inactive at transfected hm5 receptors. Partial agonist activity at hm1 and hm3 muscarinic receptors was present even after using alkylation to reduce receptor numbers to levels comparable to that level found in the hm5 cell line. Thus, with functional assays either with brain tissue or with transfected cell lines, L-689,660 was shown to be an agonist for the M1 and M3 receptors but not for M5 or M4 receptors.

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Indication	Highest Phase	Country/Location	Organization	Date
Alzheimer Disease	Discovery	United States	Merck & Co., Inc.	-
Pain	Discovery	United States	Merck & Co., Inc.	-

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