Psychopharmacology (2003) 170:17–22 DOI 10.1007/s00213-003-1465-3 ORIGINAL INVESTIGATION Abdeslam Chagraoui · Philippe Protais · Thierry Filloux · Elisabeth Mocar Agomelatine(S 20098) antagonizes the penile erections induced by the stimulation of 5-HT 2C receptors in Wistar rats Received: 12 July 2002 / Accepted: 28 February 2003 / Published online: 7 August 2003  Springer-Verlag 2003 Abstract Agomelatine, an antidepressant with melatonin agonist and 5-HT 2C antagonist properties, as well as two of its main metabolites, S 21517 (N-[2-(7-hydroxy-1- naphtyl)ethyl]acetamide) and S21540 (N-[2-(3-hydroxy- 7-methoxynaphtalen-1-yl)ethyl]acetamide), have been as- sessed in vitro on pig choroid plexus preparations to determine their affinities for 5-HT 2C receptors and their effects on inositol phosphate production. These com- pounds were also tested for their ability to inhibit the penile erections induced by the 5-HT 2C receptor agonists, m-(chlorophenyl)piperazine (mCPP, 0.75 mg/kg, SC) and Ro 60-0175 (2.5 mg/kg, SC) in Wistar rats. These in vivo effects were compared to those of melatonin and the 5-HT antagonists pizotifen and SB 206,553. Agomelatine and S 21517 had moderate affinity for 5-HT 2C receptors and behaved in vitro as weak antagonists at this receptor subtype. S 21540 had a 10-fold lower affinity. Pizotifen and SB 206,553 antagonized mCPP- and Ro 60-0175- induced penile erections, suggesting that penile erections induced by mCPP or Ro 60-0175 resulted from the stimulation of 5-HT 2C receptors. Whereas increasing doses (from 1.25 to 40 mg/kg, IP) of melatonin were unable to modify the penile erections induced by mCPP and Ro 60-0175, agomelatine (from 1.25 to 40 mg/kg, IP) dose-dependently decreased mCPP- as well Ro 60-0175- induced penile erections. Furthermore, increasing doses (from 1.25 to 40 mg/kg, IP) of S 21517 and S 21540, the two main metabolites of agomelatine, did not affect the penile erections induced by mCPP and Ro 60-0175. Considering the similar activity of melatonin and agome- latine at melatonin receptors, these data suggested that the reported effects were not due to the stimulation of melatonin receptors and that, contrary to melatonin, agomelatine exerted 5-HT 2C receptor antagonist proper- ties in addition to its agonist activity at melatonin receptors. Finally, neither S 21517 nor S 21540 seemed to participate to the observed inhibition of penile erec- tions by agomelatine. Keywords Melatonin · Agomelatine · 5-HT 2C receptors · Penile erections · Rats Introduction Agomelatine (S 20098; N[2-(7-methoxy-1-naphthyl)eth- yl] acetamide) is a new antidepressant active in rodent models predictive of antidepressant properties (Bertaina- Anglade et al. 2002; Bourin et al. 2002; Papp et al. 2003), and with demonstrated clinical efficacy in major depres- sive disorders (Lôo et al. 2002). It has been shown that its efficacy cannot be exclusively attributed to its agonist activity on MT 1 /MT 2 receptors. Agomelatine has high affinities for cloned human MT 1 and MT 2 melatonin receptor subtypes (K i =6.1510 11 M and 2.6810 10 M, respectively) comparable to melatonin affinities for these receptors (Yous et al. 1992; Conway et al. 2000). A number of studies have also demonstrated the chronobi- otic activity of agomelatine. Thus, agomelatine resyn- chronized experimentally disrupted circadian rhythms in rodents (Armstrong et al. 1993; Redman et al. 1995; Martinet et al. 1996; Van Reeth et al. 1997), and this effect is related to its agonist activity on melatonin receptors of the SCN (Ying et al. 1996; Redman and Francis, 1998). Though an evaluation of the interaction of agomelatine with a broad range (>80) of receptors and enzymes, it has been demonstrated that agomelatine had Dr. Protais died in 2002 A. Chagraoui ( ) ) · P. Protais Laboratoire de Physiologie (VACOMED), U.F.R. de MØdecine-Pharmacie, 22 Boulevard Gambetta, 76183 Rouen Cedex 1, France e-mail: abdeslam.chagraoui@univ-rouen.fr Tel.: +33-2-35148366 Fax: +33-2-35148367 T. Filloux MDS Pharma Services, 18 Chemin des Aulx, 1228 Plan-les-Ouates, Geneva, Switzerland E. Mocar Institut de Recherches Internationales Servier, IRIS, 6 Place des PlØiades, 92415 Courbevoie Cedex, France