In vivo muscarinic cholinergic mediated effects of Lu 25-109, a M1 agonist and M2/M3 antagonist in vitro.

Abstract

Lu 25-109 [5-(2-ethyl-2H-tetrazol-5-yl)-1,2,3,6-tetrahydro-1-methylpyridine] , has M agonistic and M2/M3 antagonistic effects at muscarinic receptors in vitro; a pharmacological profile that may be beneficial in treatment of Alzheimer's disease. In the present study, we compare functional in vivo effects of Lu 25-109 and reference compounds in animal models of muscarinic cholinergic function. Lu 25-109 substituted completely for the discriminative stimulus effects of (-)-7-methyl-3-(2-propynyloxy)-4,5,6,7-tetrahydroisothiazolo -[4, 5-c]pyridine (Lu 26-046), a partial M1/M2 agonist, but only weakly for the effects of the non-selective M1/M2/M3 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 stimulus. 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 potency. Unlike non-selective muscarinic agonists and acetylcholinesterase inhibitors, Lu 25-109 did not induce hypothermia, tremor or salivation in mice. Spontaneous locomotor activity and motor co-ordination were inhibited only at high doses. Lu 25-109 had no effect on mean blood pressure in anaesthetized rats. Lu 25-109 and O-Me-THPO produced a significant increase in heart rate. The maximum increase was 37%. In anaesthetized cats, increasing i.v. doses of Lu 25-109 were without effect on the mean blood pressure, except for a short lasting (<2 min) depressor effect following the IV injection. Furthermore, Lu 25-109 did not attenuate the reflex mechanisms restoring blood pressure following orthostasis in cats. In conclusion, the drug discrimination studies suggest a unique activity profile of Lu 25-109, and the in vivo profile suggests none or a very low frequency of unwanted cholinergic mediated effects.

• Authors: C Sánchez, J Arnt, M Didriksen, N Dragsted, S Moltzen Lenz, J Matz
• Journal: Psychopharmacology (Psychopharmacology (Berl)) Vol. 137 Issue 3 Pg. 233-40 (Jun 1998) ISSN: 0033-3158 [Print] Germany
• PMID: 9683000 (Publication Type: Journal Article)

Chemical References

• LU 25-109-T
• Muscarinic Agonists
• Muscarinic Antagonists
• Pyridines
• Receptor, Muscarinic M1
• Receptor, Muscarinic M2
• Receptor, Muscarinic M3
• Receptors, Cholinergic
• Receptors, Muscarinic
• Tetrazoles

Topics

• Animals
• Arousal (drug effects)
• Blood Pressure (drug effects)
• Cats
• Discrimination Learning (drug effects)
• Dose-Response Relationship, Drug
• Female
• Male
• Mice
• Mice, Inbred Strains
• Motor Activity (drug effects)
• Muscarinic Agonists (pharmacology)
• Muscarinic Antagonists (pharmacology)
• Pyridines (pharmacology)
• Rats
• Rats, Wistar
• Receptor, Muscarinic M1
• Receptor, Muscarinic M2
• Receptor, Muscarinic M3
• Receptors, Cholinergic (drug effects)
• Receptors, Muscarinic (drug effects)
• Tetrazoles (pharmacology)