Preliminary communication Synthesis, computational studies and preliminary pharmacological evaluation of 2e[4-(aryl substituted) piperazin-1-yl] N, N-diphenylacetamides as potential antipsychotics Sushil Kumar a, * , A.K. Wahi a , Ranjit Singh b a Drug Design & Medicinal Chemistry Research Laboratory, College of Pharmacy, IFTM, Moradabad-244001, UP, India b School of Pharmaceutical Sciences, Shobhit University, Meerut, UP, India article info Article history: Received 19 July 2010 Received in revised form 15 July 2011 Accepted 16 July 2011 Available online 22 July 2011 Keywords: N, N-diphenylacetamide Arylpiperazines Computational studies Antipsychotic activity Dopamine and Serotonin antagonists abstract A series of 2-[4-(aryl substituted) piperazin-1-yl] N, N-diphenylacetamides have been synthesized and the target compounds (3aej) were evaluated for atypical antipsychotic activity in apomorphine induced climbing, 5-HTP induced head twitches behavior and catalepsy studies in mice. The physicochemical similarity of the target compounds with respect to standard drugs clozapine, ketanserin and risperidone was calculated by using software programs. Among them, compound 3e showed maximum atypical antipsychotic like profile. Ó 2011 Elsevier Masson SAS. All rights reserved. 1. Introduction Schizophrenia is a complex psychological disorder affecting about 1% of the population worldwide [1,2]. The use of classical antipsychotics (phenothiazines, haloperidol, etc.) for the treatment of schizophrenia is associated with severe mechanism related side effects including induction of acute extra pyramidal symptoms [3,4]. Classical or typical antipsychotics share the ability to block D 2 dopamine receptor and their effectiveness in the treatment of positive symptoms of schizophrenia [5]. The adverse effects pre- sented by classical antipsychotics, along with their ineffectiveness in the treatment of negative symptoms of schizophrenia has encouraged the search for atypical antipsychotic drugs. It has been observed that clozapine and other antipsychotic drugs which show a reduced propensity for the development of EPS have demon- strated a higher affinity for the 5-HT 2 receptor than the D 2 receptor [6]. The mechanism of their action is still controversial, since there are several models explaining ‘atypicality’ by specific drug action on subclasses of serotonergic, glutamatergic, muscarinic or a-adrenergic receptors. It was hypothesized that a combination of serotonin 5-HT 2 and dopamine D 2 receptor antagonism to play critical role in the mechanism of action of atypical antipsychotic drugs. This so-called ‘serotonin-dopamine’ hypothesis has become a useful model for developing new antipsychotics to achieve superior efficacy with a lower incidence of extra pyramidal side effects compared to classical antipsychotics [7,8]. This model suggests the ratio of 5-HT 2A to D 2 receptor affinities to be the major determinant of a drug’s possibility to behave as an atypical antipsychotic [9]. Arylpiperazine derivatives display diverse phar- macological activity which can be mediated by different subpop- ulations of serotonin, dopamine and aderenergic receptors [10e15]. Their general chemical structure consists of the arylpiperazine moiety connected by an alkyl chain with the terminal amide or imide fragment (Chart 1) [16e21]. In view of these observations, we herein report the synthesis, computational studies of some new arylpiperazines and evaluate them for a possible atypical antipsy- chotic potential. 2. Results and discussion 2.1. Synthesis of compounds The new arylpiperazines were prepared using the pathway shown in Scheme 1 . The substituent of the compounds is given in * Corresponding author. Tel.: þ91 591 2360817; fax: þ91 591 2360818. E-mail address: sushilmpharm@rediffmail.com (S. Kumar). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2011.07.028 European Journal of Medicinal Chemistry 46 (2011) 4753e4759