Behavioral and Neurochemical Profile of Some Novel Phenacyl Based Isonipecotamide Derivatives
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Behavioral and neurochemical profile of some novel phenacyl based isonipecotamide derivatives Shamim Akhtar1*, Muhammad Arif1, Nousheen Mushtaq1, Zafar Saeed Saify2 Ahsaan Ahmed1, Darakhshan Jabeen Haleem3 and Arfa Akram4 1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Karachi, Karachi, Pakistan 2HEJ Research Institute of Chemistry, University of Karachi, Karachi, Pakistan 3Centre of Neuropharmacology, Department of Biochemistry, University of Karachi, Karachi, Pakistan 4Federal 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 The biogenic amines (i.e. 5-hydroxytrptamine) control different behaviors related to central nervous system in Depression is a major disease affecting 13-20% of the man and animals. These amines act as neurotransmitters population world wide (Licinio and Wong 1999). The and behave as buffers or mediators for passing the nerve mood elevating properties of Seeletium fortuosum have impulses across the synaptic cleft. Deficiency of these been attributed to mesembrine (A), an alkaloid with chemicals at the receptor site may cause different potent selective serotonin (5-HT) reuptake activity (Van behavioral disorders (Schildkraut, 1978) such as Vyke and Gericke 2000) and one of the synthesized depression, extreme excitation, sleep exhilaration, awake- compounds (B) resembles this alkaloid. fullness, etc. Out of these disorders “depression” is very common and reported as “common cold” (Wells et al., OCH3 1989). Most of the drugs which are synthetic in nature are OCH employed for the treatment of these disorders either as 3 OCH3 OCH antipsyschotic or serotonergic. In this context piperidine 3 based analogs have been developed and were found effective in the treatments of various neurological C H disorders (Barlocco et al., 2001; Michael et al., 1999). O C H Considerable works have been carried out on piperidine N derivatives as neuroactive agents from the past decade O N O and were found to be potent as 5-HT1A and 5-HT2A OCH3 C receptors antagonists (Carr et al., 2000; Lavielle et al., 2001; Luca et al, 2005; Annemarie et al., 2009). These NH2 (A) (B) substances were evaluated in treating various conditions Arecoline is a component of Areca catechu, widely used of psychoses and schizophrenia. In exploring CNS active as a chewing nut with a reputation of having anti-tumor, agents, alkyl and aryl derivatives of piperidine have been anti-oxidant and anti-depressant activities and also having synthesized and proved to be effective in the treatment of acetylcholine-estrase (ACE) inhibitory activity (Gilani et psychiatric illness and other related disorders (Shipe et al., 2006). As arecoline is a component of beetle nut and al., 2008, Dutta et al., 1998; Jordi et al., 1996). However itself a member of piperidine ring system, it is proposed with reference to Parkinson and Alzheimer’s diseases, it that N-substituted derivatives of piperidine carboxamide was reported (Choi et al., 2000, Wagner et al., 2004; Cole would exhibit antidepressant activity via serotonin re- and Vasser, 2008) that piperidine compounds exhibited a uptake mechanism on the basis of SAR. ten-fold increase in dopamine DA receptor reuptake inhibition at the DAT (dopamine transporter). *Corresponding author: e-mail: [email protected] 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 Fedouloff and coworkers (1998) reported 5-HT4 receptor appeared on mixing the reactants and in some cases after antagonist from isonipecotamide. The work was followed refluxing on water bath and setting aside at room by other scientists to develop piperidine derivatives useful temperature. The completion of reaction was monitored in the treatment of several CNS disorders (Hossnor et al., by TLC using CHCl3-MeOH as solvent system in varying 1998; Mathias et al., 2010; Vinaya et al., 2010). ratios. The resulting products were filtered and washed with warm acetone to remove the unreacted starting In search of structure-activity relationship a series of materials. The products thus obtained were recrystallized novel nipecotamide and isonipecotamide derivatives have from methanol at least three times to ensure purity and to been synthesized by our group (Saify, et al., 1999; Saify improve color and shape of the crystals. et al., 2005; Shamim et al., 2006; Mushtaq et al, 2007) and were studied for different pharmacological activities. 1-[2-(3,4-dihydroxyphenyl)-2-oxoethyl)]-4- Most of these compounds exhibited pronounced results. carboxamide piperidinium chloride (II) In view of the above noted significant results, our group Gray crystalline powder (40%) were obtained from o carried out the synthesis of some more new phenacyl methanol with m.p. 222-224 C. The spectra of the derivatives of isonipecotamide. These newly synthesized condensed product (II) displayed the characteristic -1 compounds were subjected for their behavioral effects as absorption band at λmax.(KBr)cm 3384(CONH2), well as for neurochemical estimations. 2931(OH, broad), 1668(C=O), 1429(CH2). Absorptions at 1587, 1102 and 756-634 confirmed the aromatic system MATERIALS AND METHODS while its ultraviolet spectrum exhibited the maxima at λmax 309, 351.2 and 389.6 nm. The EIMS of (II) showed The chemicals and solvents used were purchased from M+ 279 which gave the mass measurement of the Sigma Co., (Aldrich, London) and Merck. The melting molecular formula C14H19N2O4. The 1HNMR spectrum of points of the compounds were recorded in glass capillary (II) showed signals at δ: 1.51 (m, 1H, H-4), 1.61 (m,4H, tubes on Gallenkamp melting point apparatuses and were H-3,5), 2.03 (m, 4H, H-2, 6), 3.62(s 2H, H-2), 6.79 (d, uncorrected. Structures of these newly synthesized J=8.14 Hz, 1H, H-5´), 7.38 (dd, J, 1.93Hz, 5.3 Hz, 1H, H- compounds were elucidated by different spectral studies. 6´), 7.42(d, J=2.72 Hz, 1H, H-2´), 7.21 (s,1H, H-OH), 6.72 (s, 1H, H-OH), indicating the aromatic ring. Thus on 1 the basis of the above spectroscopic data, the condensed H NMR spectra were taken in CDCl3 and DMSO-d6 on Broker AM 300 and Broker AM 400 NMR spectrometers product (II) was formulated as 1-[2-(3,4-dihydroxy- operating at 300 and 400 MHz. The chemicals shift were phenyl)-2-oxo-ethyl]-4-carboxamide piperidinium recorded in PPM (δ) and coupling constant (J) were in chloride. Hz. Mass spectra were measured on Finnegan MAT 112 11/34 computer system. 1-[2-(3-nitrophenyl)-2-oxo-ethyl]-4-carboxamide piperidinium bromide (III) Off-white shiny crystals obtained from aqueous methanol General method for synthesis of compounds (II – V) o R1 CONH2 (40%), m.p. 243-244 C.The spectra of the condensed R2 O 4 product (III) showed the characteristic absorption band at Acetone 3 5 -1, H CX C R CONH2 NH + 2 3 λmax.(KBr)cm 3370(CONH2), 3180, 2920(C-H), 1700 Reflux 2 + 6 N _ H X (C=C), 1650(C=O). Aromatic system is indicated by the R4 2" (1) (2) CH2 peaks at 1520, 1345, 820, 730 and 670. While it’s ' O ultraviolet spectrum exhibited the maxima at λmax 191.8, 1' R1 246, and 354.2 nm. The EIMS of (III) showed M+ 292 '6 2' which gave the mass measurement of the molecular 5' 3' 4' formula C14H18N3O4. The 1HNMR spectrum of (III) R4 R2 R3 showed signals at δ: 2.49 (m, 1H, H-4), 2.54 (m,4H, H- (II - V) 3,5), 3.15 (m, 4H, H-2, 6), 5.19(s 2H, H-2), 7.90-7.96 (dd, J=7.3 Hz, 10.8 Hz, 1H, H-5´), 8.57 (d, J, 2.8 Hz, 1H, (II) R2 = R3 = OH, R1 = R4 = R5 = H, X = Cl 2 1 3 4 5 H-6´), 8.42(d, J=9.2 Hz, 1H, H-4´), 8.6 (d, J=1.2 Hz, 1H, (III) R = NO2, R = R = R = R = H, X = Br 3 1 2 4 5 H-2´), Thus on the basis of the above spectroscopic data (IV) R = NO2, R = R = R = R = H, X = Br 3 1 2 4 5 the condensed product (III) was formulated 1-[2-(3-nitro- (V) R = Br, R = R = R = R = H, X = Br phenyl)-2-oxo-ethyl]-4-carboxamide piperidinium bromide. Isonipecotamide (1) and corresponding substituted phenacyl halides (2) were dissolved in acetone in 1-[(2-(4-nitrophenyl)-2-oxoethyl)-4-carboxamide]- equimolar quantities separately in conical flask heated on piperidinium bromide (IV) water bath and then mixed together in a round bottom Mustard crystalline powder obtained from aqueous o -1, flask. The reaction mixtures were stirred on magnetic methanol (45%), m.p. 210-211 C. IR, λmax (KBr)cm stirrer for about 4 to 5 hours. Precipitates of products 3386(CONH2), 3268, 3199(C-H), 2941(C=C), 1519 706 Pak. J. Pharm. Sci., Vol.25, No.4, October 2012, pp.705-713 Shamim Akhtar et al. (C=O). Aromatic system is indicated by the peaks at Neurochemical estimations 1345, 853, 730 and 610.