IN-VIVO MUSCARINIC CHOLINERGIC MEDIATED EFFECTS OF LU-25-109, A M-1 AGONIST AND M-2 M-3 ANTAGONIST IN-VITRO/

Lu 25-109 [5-(2-ethyl-2H-tetrazol-5-yl)-1,2, 3,6-tetrahydro-1-methylpy ridine], has M-1 agonistic and M-2/M-3 antagonistic effects at muscari nic receptors in vitro; a pharmacological profile that may be benefici al in treatment of Alzheimer's disease. In the present study, we compa re functional in vivo effects of Lu 25-109 and reference compounds in animal models of muscarinic cholinergic function. Lu 25-109 substitute d completely for the discriminative stimulus effects of oxy)-4,5,6,7-t etrahydroisothiazolo-[4,5-c]pyridine (Lu 26-046), a partial M-1/M-2 ag onist, but only weakly for the effects of the non-selective M-1/M-2/M- 3 agonist 3-methoxy-4,5,6,7-tetrahydro-isoxazolo [4, 5-c] pyridine (O- Me-THPO). Lu 25-109 did not reverse O-Me-THPO-induced discriminative s timulus. Tacrine did not substitute for any of the training drugs. Lu 25-109 did not substitute in (-)-nicotine trained rats. Lu 25-109 did not antagonize oxotremorine-induced hypothermia, tremor and salivation in mice and antagonized physostigmine-induced lethality with low pote ncy. Unlike non-selective muscarinic agonists and acetylcholinesterase inhibitors, Lu 25-109 did not induce hypothermia, tremor or salivatio n in mice. Spontaneous locomotor activity and motor co-ordination were inhibited only at high doses. Lu 25-109 had no effect on mean blood p ressure in anaesthetized rats. Lu 25-109 and O-Me-THPO produced a sign ificant increase in heart rate. The maximum increase was 37%. In anaes thetized cats, increasing IV doses of Lu 25-109 were without effect on the mean blood pressure, except for a short lasting (<2 min) depresso r effect following the IV injection. Furthermore, Lu 25-109 did not at tenuate the reflex mechanisms restoring blood pressure following ortho stasis in cats. In conclusion, the drug discrimination studies suggest a unique activity profile of Lu 25-109, and the in vivo profile sugge sts none or a very low frequency of unwanted cholinergic mediated effe cts.