L-689,660, a novel cholinomimetic with functional selectivity for M1 and M3 muscarinic receptors.
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.
Hargreaves
R J
RJ
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex.
McKnight
A T
AT
Scholey
K
K
Newberry
N R
NR
Street
L J
LJ
Hutson
P H
PH
Semark
J E
JE
Harley
E A
EA
Patel
S
S
Freedman
S B
SB
D000818:Animals; D001665:Binding Sites; D001643:Bridged Bicyclo Compounds / Q000378:metabolism* / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002540:Cerebral Cortex / Q000378:metabolism; D005728:Ganglia, Sympathetic / Q000378:metabolism; D007765:Lacrimal Apparatus / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism; D010277:Parasympathomimetics / Q000378:metabolism* / Q000494:pharmacology; D011719:Pyrazines / Q000378:metabolism* / Q000494:pharmacology; D011812:Quinuclidines / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism*; D013388:Succinimides / Q000494:pharmacology; D013876:Thiophenes
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D010277:Parasympathomimetics; D011719:Pyrazines; D011812:Quinuclidines; D011976:Receptors, Muscarinic; D013388:Succinimides; D013876:Thiophenes; C076265:L 689660; C001886:2-ethyl-8-methyl-2,8-diazaspiro(4,5)decane-1,3-dione; C059240:cevimeline