Zacopride Explained

Zacopride is a potent antagonist at the 5-HT3 receptor[1] and an agonist at the 5-HT4 receptor.[2] It has anxiolytic[3] and nootropic effects in animal models,[4] with the (R)-(+)-enantiomer being the more active form.[5] It also has antiemetic[6] and pro-respiratory effects, both reducing sleep apnea[7] and reversing opioid-induced respiratory depression in animal studies.[8] Early animal trials have also revealed that administration of zacopride can reduce preference for and consumption of ethanol.[9]

Zacopride was found to significantly increase aldosterone levels in human subjects for 180 minutes at a dose of 400 micrograms. It is thought to do this by stimulating the 5-HT4 receptors on the adrenal glands. Zacopride also stimulated aldosterone secretion when applied to human adrenal glands in vitro. No significant changes were observed in renin, ACTH, or cortisol levels.

Zacopride has been tested in clinical trials for the treatment of schizophrenia, but was found unsuccessful.[10]

Notes and References

  1. Smith WW, Sancilio LF, Owera-Atepo JB, Naylor RJ, Lambert L . Zacopride, a potent 5-HT3 antagonist . The Journal of Pharmacy and Pharmacology . 40 . 4 . 301–2 . April 1988 . 2900319 . 10.1111/j.2042-7158.1988.tb05253.x . 32862252 .
  2. Lefebvre H, Contesse V, Delarue C, Soubrane C, Legrand A, Kuhn JM, Wolf LM, Vaudry H . 6 . Effect of the serotonin-4 receptor agonist zacopride on aldosterone secretion from the human adrenal cortex: in vivo and in vitro studies . The Journal of Clinical Endocrinology and Metabolism . 77 . 6 . 1662–6 . December 1993 . 10.1210/jcem.77.6.8263156 . 8263156 .
  3. Costall B, Domeney AM, Gerrard PA, Kelly ME, Naylor RJ . Zacopride: anxiolytic profile in rodent and primate models of anxiety . The Journal of Pharmacy and Pharmacology . 40 . 4 . 302–5 . April 1988 . 2900320 . 10.1111/j.2042-7158.1988.tb05254.x . 1083706 .
  4. Fontana DJ, Daniels SE, Eglen RM, Wong EH . Stereoselective effects of (R)- and (S)-zacopride on cognitive performance in a spatial navigation task in rats . Neuropharmacology . 35 . 3 . 321–7 . March 1996 . 8783207 . 10.1016/0028-3908(96)00191-8 . 12818436 .
  5. Young R, Johnson DN . Anxiolytic-like activity of R(+)- and S(-)-zacopride in mice . European Journal of Pharmacology . 201 . 2–3 . 151–5 . August 1991 . 1686755 . 10.1016/0014-2999(91)90338-Q .
  6. Yamakuni H, Nakayama H, Matsui S, Imazumi K, Matsuo M, Mutoh S . Inhibitory effect of zacopride on Cisplatin-induced delayed emesis in ferrets . Journal of Pharmacological Sciences . 101 . 1 . 99–102 . May 2006 . 16651699 . 10.1254/jphs.SCJ05007X . free .
  7. Carley DW, Depoortere H, Radulovacki M . R-zacopride, a 5-HT3 antagonist/5-HT4 agonist, reduces sleep apneas in rats . Pharmacology, Biochemistry, and Behavior . 69 . 1–2 . 283–9 . 2001 . 11420096 . 10.1016/S0091-3057(01)00535-4 . 11848748 .
  8. Meyer LC, Fuller A, Mitchell D . Zacopride and 8-OH-DPAT reverse opioid-induced respiratory depression and hypoxia but not catatonic immobilization in goats . American Journal of Physiology. Regulatory, Integrative and Comparative Physiology . 290 . 2 . R405-13 . February 2006 . 16166206 . 10.1152/ajpregu.00440.2005 . 224414 .
  9. Knapp DJ, Pohorecky LA . Zacopride, a 5-HT3 receptor antagonist, reduces voluntary ethanol consumption in rats . Pharmacology, Biochemistry, and Behavior . 41 . 4 . 847–50 . April 1992 . 1594653 . 10.1016/0091-3057(92)90237-A . 45436887 .
  10. Newcomer JW, Faustman WO, Zipursky RB, Csernansky JG . Zacopride in schizophrenia: a single-blind serotonin type 3 antagonist trial . Archives of General Psychiatry . 49 . 9 . 751–2 . September 1992 . 1514881 . 10.1001/archpsyc.1992.01820090079013 .

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