BM-5, a centrally active partial muscarinic agonist with low tremorogenic activity. In vivo and in vitro studies.
The acute and chronic effects of the centrally active oxotremorine analog, BM-5, [N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)-acetamide] were examined in rats and mice. In vivo studies in mice and rats indicated that this compound is a partial muscarinic agonist with large regional differences in its efficacy: BM-5 produced low tremor in doses which evoke full salivary response. The maximal tremor response to BM-5 was much smaller than that produced by oxotremorine, while the maximal salivary response to BM-5 was greater than that evoked by oxotremorine. The tremor response to BM-5 was bell-shaped, the peak dose being around 2 mg/kg. In contrast, the salivary response increased with increasing doses of BM-5. The apparent muscarinic antagonist properties of higher doses of BM-5 were specific to the striatum in which BM-5 (0.05-10 mg/kg) caused significant decreases in the level of acetylcholine while these levels were unaltered in the cerebral cortex, hippocampus, and brainstem. Pretreatment of rats with BM-5 (5 mg/kg) also prevented the increase in striatal acetylcholine induced by oxotremorine (0.75 mg/kg). Chronic treatment of mice with BM-5 (0.2-2 mg/kg) for 14 days also showed that BM-5 at higher doses, behaved as an antagonist, since it caused supersensitivity to oxotremorine on the tremor response. In addition, the number of receptor sites, as measured by binding of 3H-3-quinuclidinyl benzilate (3H-3-QNB), was increased in the striatum while no similar increase was observed in other brain areas.(ABSTRACT TRUNCATED AT 250 WORDS)
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D002794:Choline / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D051379:Mice; D010095:Oxotremorine / Q000494:pharmacology; D010277:Parasympathomimetics / Q000378:metabolism / Q000494:pharmacology*; D011759:Pyrrolidines / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D012472:Salivation / Q000187:drug effects; D014202:Tremor / Q000139:chemically induced*
D010277:Parasympathomimetics; D011759:Pyrrolidines; D010095:Oxotremorine; C038672:N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide; D002794:Choline; D000109:Acetylcholine