Pak. J. Pharm. Sci., Vol.25, No.4, October 2012, pp.705-713 705 Behavioral and neurochemical profile of some novel phenacyl based isonipecotamide derivatives Shamim Akhtar 1 *, Muhammad Arif 1 , Nousheen Mushtaq 1 , Zafar Saeed Saify 2 Ahsaan Ahmed 1 , Darakhshan Jabeen Haleem 3 and Arfa Akram 4 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Karachi, Karachi, Pakistan 2 HEJ Research Institute of Chemistry, University of Karachi, Karachi, Pakistan 3 Centre of Neuropharmacology, Department of Biochemistry, University of Karachi, Karachi, Pakistan 4 Federal Urdu University of Arts, Science and Technology, Karachi, Pakistan Abstract: Study of natural products led to the development of new molecules of potential biological activity. Piperidine nucleus constitutes one of the components of various alkaloids and drugs. During the course of our project regarding the synthesis of derivatives of piperidine carboxamide to study the effects of these compounds as anti-depressive agents, some of the compounds exhibited significant effects at all three doses, through open field activity thus establishing a direct relationship between dose and locomotion. Moreover, these compounds have also shown the decreased level of 5- HT alone with increased level of dopamine as an indication of their antagonism towards 5-HT receptor. Keywords: Neurochemical Profile, neurotransmitters, biogenic amines, catecholamine, indolamine, antagonism, depression. INTRODUCTION Depression is a major disease affecting 13-20% of the population world wide (Licinio and Wong 1999). The mood elevating properties of Seeletium fortuosum have been attributed to mesembrine (A), an alkaloid with potent selective serotonin (5-HT) reuptake activity (Van Vyke and Gericke 2000) and one of the synthesized compounds (B) resembles this alkaloid. OCH 3 OCH 3 O OCH 3 OCH 3 C C O N OCH 3 N C NH 2 H H O (A) (B) Arecoline is a component of Areca catechu, widely used as a chewing nut with a reputation of having anti-tumor, anti-oxidant and anti-depressant activities and also having acetylcholine-estrase (ACE) inhibitory activity (Gilani et al., 2006). As arecoline is a component of beetle nut and itself a member of piperidine ring system, it is proposed that N-substituted derivatives of piperidine carboxamide would exhibit antidepressant activity via serotonin re- uptake mechanism on the basis of SAR. The biogenic amines (i.e. 5-hydroxytrptamine) control different behaviors related to central nervous system in man and animals. These amines act as neurotransmitters and behave as buffers or mediators for passing the nerve impulses across the synaptic cleft. Deficiency of these chemicals at the receptor site may cause different behavioral disorders (Schildkraut, 1978) such as depression, extreme excitation, sleep exhilaration, awake- fullness, etc. Out of these disorders “depression” is very common and reported as “common cold” (Wells et al., 1989). Most of the drugs which are synthetic in nature are employed for the treatment of these disorders either as antipsyschotic or serotonergic. In this context piperidine based analogs have been developed and were found effective in the treatments of various neurological disorders (Barlocco et al., 2001; Michael et al., 1999). Considerable works have been carried out on piperidine derivatives as neuroactive agents from the past decade and were found to be potent as 5-HT 1 A and 5-HT 2 A receptors antagonists (Carr et al., 2000; Lavielle et al., 2001; Luca et al, 2005; Annemarie et al., 2009). These substances were evaluated in treating various conditions of psychoses and schizophrenia. In exploring CNS active agents, alkyl and aryl derivatives of piperidine have been synthesized and proved to be effective in the treatment of psychiatric illness and other related disorders (Shipe et al., 2008, Dutta et al., 1998; Jordi et al., 1996). However with reference to Parkinson and Alzheimer’s diseases, it was reported (Choi et al., 2000, Wagner et al., 2004; Cole and Vasser, 2008) that piperidine compounds exhibited a ten-fold increase in dopamine DA receptor reuptake inhibition at the DAT (dopamine transporter). *Corresponding author: e-mail: dr_shamimakhtar58@yahoo.com