M1 Receptor Agonist Activity Is Not a Requirement for Muscarinic Antinociception

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Vol. 281, Issue 2, 868-875, 1997

M₁ Receptor Agonist Activity Is Not a Requirement for Muscarinic Antinociception

Malcolm J. Sheardown, Harlan E. Shannon, Michael D. B. Swedberg, Peter D. Suzdak, Frank P. Bymaster, Preben H. Olesen, Charles H. Mitch, John S. Ward and Per Sauerberg

Novo Nordisk A/S, Health Care Discovery, Novo Nordisk Park, DK-2760, Måløv, Denmark (M.J.S., M.D.B.S., P.D.S., P.H.O., P.S.) and Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (H.E.S., F.P.B., C.H.M., J.S.W.)

The analgesic effects of a series of muscarinic agonists were investigated by use of the mouse acetic acid writhing, grid-shock,hot-plate and tail-flick tests. The compounds tested were oxotremorine,pilocarpine, arecoline, aceclidine, RS86 and four 3-3(substituted-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridines (substituted TZTP), these being propoxy-TZTP, 3-Cl-propylthio-TZTP,xanomeline (hexyloxy-TZTP) and hexylthio-TZTP. These agonistswere also assayed for their ability to displace [³H]oxotremorine-M and [³H]pirenzepine binding and for their functional selectivity atpharmacologic M₁, M₂ and M₃ receptors. These compounds all produceddose-dependent antinociceptive effects in all of the mouse analgesiatests. The effects of oxotremorine in the writhing test were fullyantagonized by the muscarinic antagonist scopolamine (0.1 mg/kg),but only partially antagonized by methscopolamine (10 mg/kg) andunaffected by the opioid antagonist naltrexone. 3-Cl-propylthio-TZTPand propoxy-TZTP had virtually no effect at the M₁ receptor subtypeas measured by the human m₁ clone expressed in baby hamster kidneycells or the rabbit vas deferens assay. These compounds, however,were more potent in the analgesia tests than the selective M₁agonists xanomeline and hexylthio-TZTP. These data suggest thatmuscarinic analgesia is mediated by central muscarinic receptors.However, activity at the M₁ receptor subtype is not a requirementfor antinociceptive activity.

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