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Cholinomimetic activities of minaprine

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Summary

The cholinomimetic activities of the antidepressant drug minaprine have been investigated, in vitro and in vivo, in rodents. Minaprine, and its metabolite SR 95070B [3-(2-morphohnoethylamino)-4-methyl-6-(2-hydroxyphenyl) pyridazine hydrochloride] selectively displaced [3H]-pirenzepine from its cortical and hippocampal binding sites, and only weakly inhibited the binding of [3H]-N-methylscopolamine in either the rat cerebellum, heart and salivary glands, or the guinea-pig ileum. In mice, none of these drugs induced the typical cholinergic side-effects up to lethal doses. Minaprine and SR 95070B antagonized rotations induced by an intrastriatal injection of pirenzepine in mice, after intraperitoneal and/or oral administration. Minaprine also antagonized atropine-induced mydriasis in mice. Both minaprine and SR 95070B potentiated the tremorigenic effect of oxotremorine without inducing tremor when injected alone.

Finally, minaprine and SR 95070B, after parenteral and/or oral injection, antagonized the scopolamine-induced deficit in passive avoidance learning, and enhanced short-term retention in the social memory test, in rats. The muscarinic agonists arecoline, oxotremorine and RS 86 [2-ethyl-8-methyl-2,8 diazaspiro-4,5 decan-1,3 dion hydrobromide], as well as the acetylcholine esterase inhibitors physostigmine and tacrine were active in most of these models.

These results indicate that minaprine, and its metabolite SR 95070B, have cholinomimetic activities which could be, at least in part, mediated by their selective affinity for M1 muscarinic receptors. Thus minaprine could represent a potential useful drug for the treatment of senile dementias and cognitive impairments occurring in elderly people.

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References

  • Araki H, Nojiri M, Kimura M, Aihara H (1987) Effects of minaprine on delayed neuronal death in mongolian gerbils with occluded common carotid arteries. J Pharmacol Exp Ther 242:686–691.

    Google Scholar 

  • Araujo DM, Lapchak PA, Robitaille Y, Gauthier S, Quirion R (1988) Differential alteration of various cholinergic markers in cortical and subcortical region of human brain in Alzheimer's disease. J Neurochem 50:1914–1923.

    Google Scholar 

  • Bartus RT, Dean RL, Beer B, Lippa S (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217:408–417.

    Google Scholar 

  • Birdsall NJ, Burgen AS, Hulme EC, Stockton JM, Zigmond MJ (1983) The effect of McN-A-343 on muscarinic receptors in the cerebral cortex and heart. Br J Pharmacol 78:257–259.

    Google Scholar 

  • Biziere K, Worms P, Kan JP, Mandel P, Garattini S, Roncucci R (1985) Minaprine, a new drug with antidepressant properties. Drugs Exp Clin Res 11:831–840.

    Google Scholar 

  • Biziere K, Gueudet C, Worms P (1986) Further evidence for a cholinomimetic activity of minaprine. Br J Pharmacol 87 (Suppl):31.

    Google Scholar 

  • Bruno G, Mohr E, Gillespie M, Fedio P, Chase TN (1986) Muscarinic agonist therapy of Alzheimer's disease: A clinical trial of RS 86. Arch Neurol 43:659–661.

    Google Scholar 

  • Caulfield MP, Higgins GA, Straughan DW (1983) Central administration of the muscarinic receptor subtype selective antagonist pirenzepine selectively impairs passive avoidance learning in the mouse. J Pharm Pharmacol 35:131–133.

    Google Scholar 

  • Chermat R, Simon P, Boissier JR (1976) Profils psychopharmacologiques de la pilocarpine, de l'oxotremorine et de l'ésérine. J Pharmacol (Paris) 7:227–240.

    Google Scholar 

  • Cumin R, Bandle EF, Gamzu E, Haefely WE (1982) Effects of a novel compound aniracetam (Ro 13–5057) upon impai red learning and memory in rodents. Psychopharmacology 78:104–111.

    Google Scholar 

  • Dantzer R, Bluthe RM, Koob GF, Le Moal M (1987) Modulation of social memory in male rats by neurohypophyseal peptides. Psychopharmacology 91:363–368.

    Google Scholar 

  • Davi H, Dupont P, Jeanniot JP, Roncucci R, Cautreels W (1981) The biotransformation of 14C-minaprine in man and five animal species. Xenobiotica 11:735–747.

    Google Scholar 

  • Dokla CPJ, Gabos P, Babrowicz JC, Rydelec L, Pereira D, Thal LJ (1987) Behavioral effects of tetrahydroaminoacridine following scopolamine pretreatment and nucleus basalis magnocellularis lesions in rats. Neurosci Abstract 13:837.

    Google Scholar 

  • Doods HN, Mathy MJ, Davidesko D, Charldorp KJ, De Jonge A, Van Zwieten PA (1987) Selectivity of muscarinic antagonists in radioligand and in vivo experiments for the putative M1, M2 and M3 receptors. J Pharmacol Exp Ther 242:257–262.

    Google Scholar 

  • Elrod K, Buccafusco JJ (1988) An evaluation of the mechanism of scopolamine-induced impairment in two passive avoidance protocols. Pharmacol Biochem Behav 29:15–21.

    Google Scholar 

  • Garattini S, Forloni GL, Tirelli S, Ladinsky H, Consolo S (1984) Neurochemical effects of minaprine, a novel psychotropic drug, on the central cholinergic system of the rat. Psychopharmacology 82:210–214.

    Google Scholar 

  • Giraldo E, Hammer R, Ladinsky H (1987) Distribution of muscarinic receptor subtypes in rat brain as determined in binding studies with AF-DX 116 and pirenzepine. Life Sci 40:833–840.

    Google Scholar 

  • Hammer R, Berrie CP, Birdsall NJ, Burgen AS, Hulme EC (1980) Pirenzepine distinguishes between different subclasses of muscarinic receptors. Nature (Lond) 293:90–92.

    Google Scholar 

  • Hammer R, Giraldo E, Schiavi GB, Monferini E, Ladinsky H (1986) Binding profile of a novel cardioselective muscarinic receptor antagonist, AFDX 116, to membranes of peripheral and brain tissues in the rat. Life Sci 38:1653–1660.

    Google Scholar 

  • Haroutunian V, Barnes E, Davis KL (1985) Cholinergic modulation of memory in rats. Psychopharmacology 87:266–271.

    Google Scholar 

  • Hershenson FM, Moos WH (1986) Drug development for senile cognitive decline. J Med Chem 29:1125–1130.

    Google Scholar 

  • Hoss W, Messner W Jr (1986) Multiple muscarinic receptors in the CNS. Significance and prospects for future research. Biochem Pharmacol 35:3895–3901.

    Google Scholar 

  • Hulme EC, Birdsall NJ, Burgen AS, Mehta P (1978) The binding of antagonists to brain muscarinic receptors. Mol Pharmacol 14:737–750.

    Google Scholar 

  • Hunter AJ, Roberts FF (1988) The effect of pirenzepine on spatial learning in the Morris water maze. Pharmacol Biochem Behav 30:519–523.

    Google Scholar 

  • Jarvik ME, Koop R (1967) An improved one-trial passive avoidance learning situation. Psychol Med 21:221–224.

    Google Scholar 

  • Johns CA, Haroutunian V, Greenwald BS, Mohs RC, Davis BM, Kanof P, Hovarth JB, Davis KL (1985) Development of cholinergic drugs for the treatment of Alzheimer's disease. Drug Dev Res 5:77–96.

    Google Scholar 

  • Kaul PN (1962) Enzyme inhibiting action of tetrahydroaminoacridine and its structural fragments. J Pharm Pharmacol 14:243–248.

    Google Scholar 

  • Kawashima K, Nabeshima T, Kameyama T (1987)Effect of minaprine on cycloheximide-induced amnesia in mice. Jap J Pharmacol 43 (Suppl):225.

    Google Scholar 

  • Kunysz EL, Michel AD, Whiting RL (1988) Functional and direct binding studies using subtype selective muscarinic receptor antagonists. Br J Pharmacol 93:491–500.

    Google Scholar 

  • Mandel RJ, Thal LJ (1988) Physostigmine improves water maze performance following nucleus basalis magnocellularis lesions in rats. Psychopharmacology 96:421–425.

    Google Scholar 

  • Mash DC, Flynn DD, Potter LT (1985) Loss of M2 muscarinic receptors in the cerebral cortex in Alzheimer's disease and experimental cholinergic denervation. Science 228:1115–1117.

    Google Scholar 

  • Murray CL, Fibiger HC (1986) Pilocarpine and physostigmine attenuate spatial memory impairments produced by lesions of the nucleus basalis magnocellularis. Behav Neurosci 100:23–32.

    Google Scholar 

  • Palacios JM, Bolliger G, Closse AM, Enz A, Gmelin G, Malanowski J (1986) The pharmacological assessment of RS 86, a potent specific muscarinic acetylcholine receptor agonist. Eur J Pharmacol 125:45–62.

    Google Scholar 

  • Passeri M, Cucinotta D, De Mello M, Biziere K (1987) Comparison of minaprine and placebo in the treatment of Alzheimer's disease end multi-infarct dementia. Int J Ger Psychiat 2:97–103.

    Google Scholar 

  • Pedata F, Moroni F, Pepeu GC (1984) Effect of nootropic agents on brain cholinergic mechanisms. Clin Neuropharmacol 7 (Suppl 1):772–773.

    Google Scholar 

  • Perio A, Terranova JP, Worms P, Bluthe RM, Dantzer R, Biziere K (1989) Specific modulation of social memory in rats by cholinomimetic and nootropic drugs, by benzodiazepine inverse agonists but not by psychostimulants. Psychopharmacology 97:262–268.

    Google Scholar 

  • Saunders J, Showell GA, Freedman SB, Hill P, Newberry N, Salamone JD, Springer JP (1987) Synthesis and characterization of all four isomers of the muscarinic agonist 2-methyl-spiro (1-azabicyclo (2.2.2) octane-3,4′-(1,3) dioxolane). J Med Chem 30:969–975.

    Google Scholar 

  • Sethy VH (1983) Effect of piracetam on high affinity choline uptake. Soc Neurosci Abstr 9:429.

    Google Scholar 

  • Spencer DG, Hovarth E, Traber J (1986) Direct autoradiographic determination of M1 and M2 muscarinic acetylcholine receptor distribution in the rat brain: Relation to cholinergic nuclei and projections. Brain Res 380:59–68.

    Google Scholar 

  • Tonnaer JADM, Van Vugt MA, De Boer T, De Graaf JS (1987) Differential interactions of muscarinic drugs with binding sites of (3H)pirenzepine and (3H)quinuclidinyl benzylate in rat brain tissue. Life Sci 40:1981–1987.

    Google Scholar 

  • Wamsley JR, Gehlert DR, Roeske WR, Yamamura HI (1984) Muscarinic antagonist binding site heterogeneity as evidenced by autoradiographic and direct labelling with (3H)QNB and (3H)pirenzepine. Life Sci 34:1395–1402.

    Google Scholar 

  • Watson M, Roeske WR, Yamamura HI (1982) (3H)pirenzepine selectively identifies a high affinity population of muscarinic cholinergic receptors in the rat cerebral cortex. Life Sci 31:2019–2023.

    Google Scholar 

  • Watson M, Yamamura HI, Roeske WR (1986) (3H)pirenzepine and (3H)QNB binding to rat cerebral cortical and cardiac muscarinic cholinergic sites. I. Characterization and regulation of agonist binding to putative muscarinic subtypes. J Pharmacol Exp Ther 237:411–418.

    Google Scholar 

  • Whitehouse J, Strubble RG, Hedren JC, Clark AW, Price DL (1985) Alzheimer's disease and related dementias: selective involvement of specific neuronal systems. Critical Rev Clin Neurobiol 1:319–339.

    Google Scholar 

  • Worms P, Gueudet C, Biziere K (1986) Induction of turning by direct intrastriatal injection of dopaminomimetic drugs in mice: Pharmacological analysis of a simple screening model. Life Sci 39:2199–2208.

    Google Scholar 

  • Worms P, Biziere K (1987) Antagonism by cholinomimetic drugs of the turning induced by intrastriatal pirenzepine in mice. Psychopharmacology 93:489–493.

    Google Scholar 

  • Wurtman RJ (1986) Strategies in the development of drugs that might be useful in cognitive disorders. Clin Neuropharmacol 9:S3-S10.

    Google Scholar 

Download references

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Author notes

  1. Kathleen Biziere

    Present address: Hoffmann-La Roche, CH-4002, Basel, Switzerland

Authors and Affiliations

  1. Neurobiology Department, Sanofi Recherche, rue du Pr. J. Blayac, F-34082, Montpellier Cedex, France

    Paul Worms, Jean-Paul Kan, Regis Steinberg, Jean-Paul Terranova, Alain Perio & Kathleen Biziere

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  1. Paul Worms
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  2. Jean-Paul Kan
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  3. Regis Steinberg
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  4. Jean-Paul Terranova
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  5. Alain Perio
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  6. Kathleen Biziere
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Worms, P., Kan, JP., Steinberg, R. et al. Cholinomimetic activities of minaprine. Naunyn-Schmiedeberg's Arch Pharmacol 340, 411–418 (1989). https://doi.org/10.1007/BF00167042

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