ISSN:
1432-2072
Keywords:
Key words Muscarinic receptors
;
Drug discrimination
;
Hypothermia
;
Tremor
;
Salivation
;
Locomotion
;
Blood pressure
;
Heart rate
;
Rodents
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Abstract Lu 25-109 [5-(2-ethyl-2H-tetrazol-5-yl)-1,2, 3,6-tetrahydro-l-methylpyridine], has M1 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 IV 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.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/s002130050615
Permalink
