Abstract
In rats allowed to eat for 2h/day and injected i.p. 30 min before feeding, MK-212, ED50=1.5 mg/kg, was two times more potent as an anorexigen than fenfluramine. However, the compounds were equiactive in the rat following p.o. administration 1.5 or 3 h before the test, while fenfluramine was more potent if the interval was extended to 6 h. In cats permitted to eat for 3 h/day, the ED50 dose (mg/kg p.o.) for MK-212 determined at 0.5, 1 and 3 h after feeding was, respectively, 15, 10 and 3 times less than that of fenfluramine. Emesis and diarrhea were frequently observed ancillary effects in cats treated with fenfluramine, whereas apparent sedation and salivation were commonly detected in animals after MK-212. In rats or cats pretreated with methergoline, the decrease in food consumption elicited by MK-212 was markedly inhibited, suggesting that the mechanism of action involves a serotoninlike effect. Compared with the marked stimulant action of amphetamine, MK-212 had only a minor and inconsistent effect on motor activity in rats and mice. Similar results were obtained with fenfluramine. MK-212 was not self-administered by rats, while the self-administration of amphetamine and morphine were demonstrated using the same experimental protocol.
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Beretta, C., Glasser, A. H., Nobili, M. B., Silvestri, R.: Antagonism of 5-hydroxytryptamine-induced bronchospasm in guinea pigs by 8β-carbobenzyloxyaminomethyl-1,6-dimethyl-10α-ergoline. J. Pharm. Pharmacol. 17, 423–428 (1965)
Clineschmidt, B. V.: 5,6-Dihydroxytryptamine: suppression of the anorexigenic action of fenfluramine. Eur. J. Pharmacol. 24, 405–409 (1973)
Clineschmidt, B. V., Lotti, V. J.: Indoleamine antagonists: relative potencies as inhibitors of tryptamine- and 5-hydroxytryptophan-evoked responses. Br. J. Pharmacol. 50, 311–313 (1974)
Clineschmidt, B. V., McGuffin, J. C., Pflueger, A. B.: Central serotonin-like activity of 6-chloro-2-(1-piperazinyl)-pyrazine (CPP; MK-212). Eur. J. Pharmacol. 44, 65–74 (1977)
Clineschmidt, B. V., McGuffin, J. C., Pflueger, A. B., Totaro, J. A.: Fenfluramine-induced enhancement of confinement motor activity: an indirect 5-hydroxytryptamine-like action? Neuropharmacology 14, 301–311 (1975)
Clineschmidt, B. V., McGuffin, J. C., Werner, A. B.: Role of monoamines in the anorexigenic actions of fenfluramine, amphetamine and p-chloromethamphetamine. Eur. J. Pharmacol. 27, 313–323 (1974)
Funderburk, W. H., Hazelwood, J. C., Ruckart, R. T., Ward, J. W.: Is 5-hydroxytryptamine involved in the mechanism of action of fenfluramine? J. Pharm. Pharmacol. 23, 468–470 (1971)
Fuxe, K., Agnati, L., Everitt, B.: Effects of methergoline on central monoamine neurons. Evidence for a selective blockade of central 5-HT receptors. Neurosci. Lett. 1, 283–290 (1975)
Garattini, S., Buczko, W., Jori, A., Samanin, R.: The mechanism of action of fenfluramine. Postgrad. Med. J. 51 [Suppl. 1], 27–35 (1975)
Gotestam, K. G., Anderson, B. E.: Self-administration of amphetamine in rats. Pharmacol. Biochem. Behav. 3, 229–233 (1975)
Jespersen, S., Scheel-Kruger, J.: Antagonism by methysergide of the 5-hydroxytryptamine-like action of toxic doses of fenfluramine in dogs. J. Pharm. Pharmacol. 22, 637–638 (1970)
Jespersen, S., Scheel-Kruger, J.: Evidence for a difference in the mechanism of action between fenfluramine- and amphetamine-induced anorexia. J. Pharm. Pharmacol. 25, 49–54 (1973)
Joy, R. J. T., Emma, C. P., Mayer, J.: New rat feeding jar: use in study of relationships of food intake and body weight. J. Appl. Physiol. 23, 589–590 (1967)
LeDouarec, J. C., Neveu, C.: Pharmacology and biochemistry of fenfluramine. In: Amphetamines and related compounds, E. Costa and S. Garattini, eds., pp. 75–105, New York, Raven Press 1970
Pinder, R. M., Brogden, R. N., Sawyer, P. R., Speight, T. M., Avery, G. S.: Fenfluramine: a review of its pharmacological properties and therapeutic efficacy in obesity. Drugs 10, 241–323 (1975)
Quock, R. M., Beal, G. A.: Fenfluramine-induced hyperthermia and stimulation in the rabbit. Res. Commun. Chem. Pathol. Pharmacol. 13, 401–409 (1976)
Samanin, R., Ghezzi, D., Valzelli, L., Garattini, S.: The effects of selective lesioning of brain serotonin or catecholamine containing neurons on the anorectic activity of fenfluramine and amphetamine. Eur. J. Pharmacol. 19, 318–322 (1972)
Southgate, P. J., Mayer, S. R., Boxall, E., Wilson, A. B.: Some 5-hydroxytryptamine-like actions of fenfluramine: a comparison with (+)-amphetamine and diethylpropion. J. Pharm. Pharmacol. 23, 600–605 (1971)
Tedeschi, D. H., Fowler, P. J., Cromley, W. H., Pauls, J. F., Eby, R. Z., Fellows, E. J.: Effects of centrally acting drugs on confinement motor activity. J. Pharm. Sci. 53, 1046–1050 (1964)
Weeks, J. R., Davis, J. D.: Chronic intravenous cannulas for rats. J. Appl. Physiol. 19, 540–541 (1964)
Woods, J. H., Tessel, R. E.: Fenfluramine: amphetamine congener that fails to maintain drug-taking behavior in the rhesus monkey. Science 185, 1067–1069 (1974)
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Clineschmidt, B.V., Hanson, H.M., Pflueger, A.B. et al. Anorexigenic and ancillary actions of MK-212 (6-chloro-2-[1-piperazinyl]-pyrazine; CPP). Psychopharmacology 55, 27–33 (1977). https://doi.org/10.1007/BF00432813
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DOI: https://doi.org/10.1007/BF00432813