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

Psychopharmacology (Berl). 1998 Jun;137(3):233-40. doi: 10.1007/s002130050615.

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.

MeSH terms

  • 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*

Substances

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