Abstract
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. Because of its regional specificity, and low tremorogenic activity, BM-5 may serve as a model compound in the search for muscarinic agonists with therepeutic value in senile dementia of the Alzheimer type.
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References
Bartus RT, Dean III RL, Beer B, Lippa AS (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217:408–417
Birdsall NJM, Burgen ASV, Hulme EC (1978) The binding of agonists to brain muscarinic receptors. Mol Pharmacol 14:723–736
Consolo S, Ladinsky H, Peri G, Garathini S (1972) Effect of central stimulants and depressants on mouse brain acetylcholine and choline levels. Eur J Pharmacol 18:251–255
Hedlund B, Abens J, Bartfai T (1983) Vasoactive intestinal polypeptide and muscarinic receptors: supersensitivity induced by long-term atropine treatment. Science 220:519–521
Jenden DJ (1965) Studies on tremorine antagonism by structurally related compounds. In: Costo E, Cote LJ, Yahr MD (eds) Biochemistry and pharmacology of the basal ganglia. Raven, New York, pp 159–170
Ladinsky H, Consolo S (1974) Determination of acetylcholine and choline by enzymatic radioassay. In: Hanin I (ed) Choline and acetylcholine: Handbook of chemical assay methods. Raven, New York, pp 1–17
Ladinsky H, Consolo S, Peri G (1974) Effect of oxotremorine and physostigmine on choline levels in mouse whole brain, spleen and cerebellum. Biochem Pharmacol 23:1187–1193
Ladinsky H, Consolo S, Bianchi S, Jori A (1976) Increase in striatal acetylcholine by picrotoxin in the rat: evidence for a gabaergic-dopaminergic cholinergic link. Brain Res 108:351–361
Ladinsky H, Consolo S, Peri G, Crunelli V, Samanin R (1977) Pharmacological evidence for a serotonergic cholinergic link in the striatum. In: Jenden DJ (ed) Cholinergic mechanisms and psychopharmacology. Plenum, New York, pp 615–629
Maayani S, Egozi Y, Pinchasi I, Sokolovsky M (1977) On the interaction of drugs with the cholinergic nervous system — IV. Tolerance to oxotremorine in mice: in vivo and in vitro studies. Biochem Pharmacol 26:1681–1687
Nordström Ö, Bartfai T (1982) Mechanism of action of the muscarinic autoreceptor in the rat hippocampus. In: Proceedings of Fourth ESN-meeting. Catania, pp 189–196
Nordström A, Alberts P, Westlind A, Undén A, Bartfai T (1983) Presynaptic antagonist — postsynaptic agonist at muscarinic cholinergic synapses: N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide. Mol Pharmacol 24:1–5
Nordström Ö, Undén A, Grimm V, Frieder B, Ladinsky H, Bartfai T (1986) In vivo and in vitro studies on a muscarinic presynaptic antagonist and postsynaptic agonist: BM-5. In: Hanin I (ed) Dynamics of cholinergic function. pp 405–414
Ögren S-O, Nordström Ö, Danielsson E, Peterson L-L, Bartfai T (1985) In vivo and in vitro studies on the potentiation of muscarinc receptor stimulation by alaproclate, a selective 5-HT uptake blocker. J Neural Transm 61:1–20
Polak RL, Meeuws MM (1966) The influence of atropine on the release and uptake of acetylcholine by the isolated cerebral cortex of the rat. Biochem Pharmacol 15:989–992
Resul B, Dahlbom R, Ringdal B, Jenden DJ (1982a) N-alkyl-N-(4-tert-amino-1-methyl-2-butnynyl)carboxamide, a new class of potent oxotremorine antagonists. Eur J Med Chem 17:317–322
Resul B, Lewander T, Ringdahl B, Zetterström T, Dahlbom R (1982b) The pharmacological assessment of a new, potent oxotremorine analogue in mice and rats. Eur J Pharmacol 80:209–215
Saelens JK, Allen MP, Simke JP (1970) Determination of acetylcholine and choline by an enzymatic assay. Arch Int Pharmacodyn Ther 186:279–286
Spiegel R, Azcona A, Wettstein A (1984) First results with RS 86, an orally active muscarinic agonist in healthy subjects and in patients with dementia. In: Wurtman RJ, Corkin SH, Growdon JH (eds) Altzheimer's disease: advances in basic research and therapies. Zürich
Szerb JC (1978) Characterization of presynaptic muscarinic receptors in central cholinergic neurons. In: Jenden DJ (ed) Cholinergic mechansims and psychopharmacology. Plenum, New York, pp 49–60
Westlind A, Grynfarb M, Hedlund B, Bartfai T, Fuxe K (1981) Muscarinic supersensitivity induced by septal lesion or chronic atropine treatment. Brain Res 225:131–141
Wise BC, Shoji M, Kuo JF (1980) Decrease or increase in cardiac muscarinic cholinergic receptor number in rats treated with metacholine or atropine. Biochem Biophys Res Commun 92:1136–1142
Wurtman RJ, Corkin SH, Growdon JN (1984) Altzheimer's disease. Zürich
Yamamura HI, Snyder SH (1974) Muscarinic cholinergic receptor binding in the longitudinal muscle of the guinea pig ileum with 3H-quinuclidinylbenzilate. Mol Pharmacol 10:861–867
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Engström, C., Undén, A., Ladinsky, H. et al. BM-5, a centrally active partial muscarinic agonist with low tremorogenic activity. Psychopharmacology 91, 161–167 (1987). https://doi.org/10.1007/BF00217056
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DOI: https://doi.org/10.1007/BF00217056