[en] The interaction with monoamine oxidase A (MAO-A) and B has been shown to be sensitive to the absolute configuration of molecules. Therefore, the aim of this study was to compare the effects of the racemic pirlindole (a selective and reversible MAO-A inhibitor) and its two enantiomers using biochemical techniques (in vitro and ex vivo determination of rat brain MAO-A and MAO-B activity) and behavioural models (forced swimming test and reserpine-induced hypothermia and palpebral ptosis test). In vitro, the MAO-A IC50 of (+/-)-pirlindole, R-(-)-pirlindole and S-(+)-pirlindole were 0.24, 0.43 and 0.18 microM, respectively. Ex vivo, their ID50 were 24.4, 37.8 and 18.7 mg/kg i.p. The differences between the three compounds were not significant, with a ratio between the two enantiomers [R-(-)/S-(+)] of 2.2 in vitro and 2.0 ex vivo. MAO-B was only slightly inhibited. In the forced swimming test and the reserpine-induced hypothermia and ptosis model, the three compounds had an antidepressant profile. In the forced swimming test, the minimal effective dose ratio between the R-(-) and the S-(+) was again around 2.0. The behavioural observations were thus clearly in accordance with the biochemical data.
Disciplines :
Pharmacy, pharmacology & toxicology
Author, co-author :
Bruhwyler, J.
Liégeois, Jean-François ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Gerardy, J.
Damas, Jacques ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Département des sciences biomédicales et précliniques
Chleide, E.
Lejeune, C.
Decamp, E.
De Tullio, Pascal ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Delarge, J.
Dresse, Albert ; Université de Liège - ULiège > Services généraux (Faculté de médecine) > Relations académiques et scientifiques (Médecine)
Geczy, J.
Language :
English
Title :
Comparative study of pirlindole, a selective RIMA, and its two enantiomers using biochemical and behavioural techniques.
Publication date :
1998
Journal title :
Behavioural Pharmacology
ISSN :
0955-8810
eISSN :
1473-5849
Publisher :
Lippincott Williams & Wilkins, London, United Kingdom
Barker EL, Blakely RD (1995). Norepinephrine and serotonin transporters. Molecular targets of antidepressant drugs. In: Psychopharmacology: the fourth generation of progress. Bloom FE, Kupfer DJ (editors). New York: Raven Press, pp. 321-323.
Blackwell B (1981). Adverse effects of antidepressant drugs. Part 1: Monoamine oxidase inhibitors and tricyclics. Drugs 21:201-219.
Bruhwyler J, Liégeois JF, Lejeune C, Rogister F, Delarge J, Gécvy J (1995). New dihenzazepine derivatives with disinhibitory and/or antidepressant potential: neurochemical and behavioural study in the open-field and forced swimming tests. Behav Pharmacol 6:830-838.
Bruhwyler J, Liégeois JF, Géczy J (1997a). Pirlindole: a selective reversible inhibitor of monoamine oxidase A. A review of its preclinical properties. Pharmacol Res 36:23-33.
Bruhwyler J, Monseu MJ, Vandekerckhove K, Géczy J (1997b). Pirlindole, a reversible and selective monoamine oxidase A inhibitor: a retrospective evaluation of its clinical antidepressant profile. Eur J Clin Res 9:225-245.
Burkard WP, Bonetti EP, Da Prada M, Martin JR, Pole P, Schaffner R et al. (1989). Pharmacological profile of moclobemide, a short-acting and reversible inhibitor of monoamine oxidase type A. J Pharmacol Exp Ther 248:391-399.
Da Prada M, Kettler R, Keller HH, Burkard WP, Muggli-Maniglio D. Haefely W (1989). Neurochemical profile of moclobemide, a short-acting and reversible inhibitor of monoamine oxidase type A. J Pharmacol Exp Ther 248:400-414.
de Tullio P, Felikidis A, Pirotte B, Liégeois JF, Stachow M, Delarge J et al. (1998). First preparative enantiomer resolution of pirlindole, a potent antidepressant drug. Helv Chim Acta 81:539-547.
De Wilde JE, Geerts S, Van Dorpe J, Bruhwyler J, Géczy J (1996). A double-blind randomized placebo-controlled study of the efficacy and safety of pirlindole, a reversible monoamine oxidase A inhibitor, in the treatment of depression. Acta Psychiat Scand 94:404-410.
Dostert P, Strolin Benedetti M, Guffroy C (1983). Different stereoselective inhibition of monoamine oxidase-B by the R-and S-enantiomers of MD780236. J Pharm Pharmacol 35:161-165.
Fowler CJ, Oreland L (1981). Substrate-and stereoselective inhibition of human brain monoamine oxidase by 4-dimethylamino-α,2-dimethylphenethylamine (FLA 336). J Pharm Pharmacol 33:403-406.
Gérardy J (1994). Effect of moclobemide on rat brain monoamine oxidase A and B: comparison with harmaline and clorgyline. Prog Neuro-Psychopharmacol Biol Psychiatry 18:793-802.
Johnston JP (1968). Some observations upon a new inhibitor of monoamine oxidase in brain tissue. Biochem Pharmacol 17:1285-1297.
Lichtfield JT, Wilcoxon F (1949). A simplified method of evaluating dose-effect experiments. J Pharmacol Exp Ther 96:99-113.
Lipper S, Murphy DL, Slater S, Buchsbaum MS (1979). Comparative behavioral effects of clorgyline and pargyline in man: a preliminary evaluation. Psychopharmacology 62:123-128.
Martorana PA, Nitz RE (1979). The new antidepressant pirlindole. A comparison with imipramine and tranylcypromine. Arzneimittel Forschung 29:946-949.
Medvedev AE, Shvedov VI, Chulkova TM, Fedotova OA, Saederup E, Squires RF (1996). Effects of the antidepressant pirlindole and its dehydroderivative on the activity of monoamine oxidase-A and on GABA-A receptors. Neurochem Res 21:1521-1526.
Porsolt RD, Bertin A, Jalfre M (1977). Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther 229:327-336.
Schraven E, Reibert E (1984). Hemmung der monoamineoxidase A und B in herz und gehirn von ratten durch amitriptylin, pargylin und pirlindol. Arzneimittel Forschung Drug Res 34:1258-1260.
Snyder SH, Hendley ED (1968). A simple and sensitive fluorescence assay for monoamine oxidase and diamine oxidase. J Pharmacol Exp Ther 163:386-392.
Strolin Benedetti M, Dostert P (1985). Stereochemical aspects of MAO interactions: reversible and selective inhibitors of monoamine oxidase. Trends Pharmacol Sci 6:246-251.
Tanghe A, Geerts S, Van Dorpe J, Brichard B, Bruhwyler J, Géczy J (1997). Double-blind randomized controlled study of the efficacy and tolerability of two reversible monoamine oxidase A inhibitors, pirlindole and moclobemide, in the treatment of depression. Acta Psychiat Scand 96:134-141.
Tedeschi DH (1969). Palpebral ptosis as an index of neuroleptic activity. In: The neuroleptics. Bloom FE, Kupfer DJ (editors). Paris: Karger, p. 55.