Review Article Antidepressant potential of nitrogen-containing heterocyclic moieties: An updated review Nadeem Siddiqui, Andalip, Sandhya Bawa, Ruhi Ali, Obaid Afzal, M. Jawaid Akhtar, Bishmillah Azad, Rajiv Kumar Department of ABSTRACT Pharmaceutical Chemistry, Depression is currently the fourth leading cause of disease or disability worldwide. Antidepressant is Faculty of Pharmacy, Jamia Hamdard approved for the treatment of major depression (including paediatric depression), obsessive-compulsive University, Hamdard disorder (in both adult and paediatric populations), bulimia nervosa, panic disorder and premenstrual Nagar, New Delhi - dysphoric disorder. Antidepressant is a psychiatric medication used to alleviate mood disorders, such as 110 062, India major depression and dysthymia and anxiety disorders such as social anxiety disorder. Many drugs produce an antidepressant effect, but restrictions on their use have caused controversy and off-label prescription a Address for correspondence: risk, despite claims of superior efficacy. Our current understanding of its pathogenesis is limited and existing Dr. Sandhya Bawa, E-mail: sandhyabawa761@ treatments are inadequate, providing relief to only a subset of people suffering from depression. Reviews of yahoo.com literature suggest that heterocyclic moieties and their derivatives has proven success in treating depression. Received : 08-02-11 Review completed : 15-02-11 Accepted : 17-02-11 KEY WORDS: Antidepressant, depression, heterocyclic epression is a chronic, recurring and potentially life- monoamine oxidase inhibitors (MAOIs, e.g. Nardil®) tricyclic D threatening illness that affects up to 20% of the population antidepressants (TCAs, e.g. Elavil). They increases the synaptic across the globe.[1] The etiology of the disease is suboptimal concentration of either two (5-HT and NE) or all three (5-HT, concentrations of the monoamine neurotransmitters serotonin NE and dopamine (DA)) neurotransmitters. The combined (5-HT) and norepinephrine (NE) in the central nervous system effect of Serotonin selective reuptake inhibitor (SSRI) (Prozac®) (CNS). It is also due to consequence of dysfunctional endocrine, and serotonin reuptake transporter (SERT) inhibitor increases immune and neurotransmitter systems.[2] synaptic concentration of 5-HT and its duration of action. Depression is a chronic condition.[3] Primary clinical Recent studies suggest that combination therapy using manifestations of depression are significant depression of bupropion, a Dopamine transporter (DAT) inhibitor, and an mood and impairment of function. Some features of depressive SSRI or Serotonin–norepinephrine reuptake inhibitor (SNRI) disorders overlap those of the anxiety disorders, including panic- offers improved efficacy in the treatment of depression compared [2] agoraphobia syndrome, severe phobias, generalized anxiety with monotherapy alone. For example, DOV-21947 (by DOV disorder, social anxiety disorder, posttraumatic stress disorder, pharmaceutical, Phase II), SEP-225289 (by Sepracor, Phase II), [5] and obsessive-compulsive disorder.[4] and NS-2359 (by NeuroSearch, Phase II). A new SNRI class of antidepressants (Cymbalta®) are also approved to treat depression [2] Recent advancement in antidepressant therapeutics include the along with anxiety (approximately 60% of patients). Access this article online The major problems of existing antidepressant drugs include Quick Response Code: delayed clinical benefit, serious side-effects, and a response in Website: less than 50% of patients.[6] Neither the pathophysiology of www.jpbsonline.org depression nor the mechanism of action of various antidepressant agents is fully understood.[7] Consequently, there is still a great DOI: need for faster-acting, safer, and more effective treatments for 10.4103/0975-7406.80765 depression. In an effort to expand beyond classical monoamine- based strategies, recent medication development activities have How to cite this article: Siddiqui N, A, Bawa S, Ali R, Afzal O, Akhtar MJ, Azad B, Kumar R. Antidepressant potential of nitrogen-containing heterocyclic moieties: An updated review. J Pharm Bioall Sci 2011;3:194-212. 194 Journal of Pharmacy and Bioallied Sciences April-June 2011 Vol 3 Issue 2 Siddique, et al.: Antidepressant potential of nitrogen containing heterocyclic moieties: An updated review focused on neurotrophic factors, glutamatergic systems, and the HN R N N hypothalamic–pituitary axis (HPA) as well as a number of other S O N less well-characterized novel targets [Table 1]. N (5) H 5a =Phenyl,5n=4-Chlorophenyl, 5o =4-Bromophenyl,5j=3-Bromophenyl, 5p =4-Nitrophenyl The present review focuses on potent heterocyclic nuclei and derived compounds showing antidepressant activity.[6] Heffernam et al.,[16] synthesized a series of 4-amino ethyl -3- Indole (phenyl sulfonyl)1-H indole(6) and screened the compound for dual-acting norepinephrine reuptake inhibitor and 5-HT2A reuptake antagonist. Compound (6a) and (6b) were potent Indole is a six-membered benzene ring fused to a five-membered inhibitors of norepinephrine reuptake and possessed modest nitrogen-containing pyrrole ring. Numerous pharmacological h -HT antagonist activity. When the amino-ethyl chain shifted active compounds have an indole nucleus such as Tryptophan 5 2A from the fourth to fifth and seventh position, it behaved as a (essential amino acid), serotonin (neurotransmitter), melatonin potent antagonist. (hormone). Indole nucleus shows potent antidepressant activity, various derivatives of indole and 5-HT serve as a template for R R 1 N 2 the development of new chemical entities that act on 5-HT 1A O O receptor and the SERT.[9] Mattson et al.,[10] synthesized some S potent serotonin reuptake inhibitors based on indole nucleus and they reported that compound (12) reveals potent hSERT N binding (Ki) 0.18 nM) in vitro. Indole nucleus is present H in many important classes of therapeutic agents.[11] Indole (6) alkaloidal analogues and indoles condensed with different (6a);R1,R2=Me [12] heterocycles showed different biological activities. Idayu (6b);R1=Et, R2=Me et al.,[13] investigated the antidepressant effect of Mitragynine (1) isolated from Mitragyna speciosa Korth. Mitragynin showed Manning et al.,[17] synthesized a series of enantiomerically pure potent antidepressant activity at dose of 10 mg/kg and 30 mg/ 1-naphthyl and 4-indolyl arylalkylamines and evaluated them for kg i.p. and reduced the immobility time of mice in both Forced binding affinities to the monoamine transporters. They designed swimming test (FST) and Tail suspension test (TST) without any (S)-4-(3, 4-dichlorophenyl)-4-(1H-indol-4-yl)-N-methylbutan- significant effect on locomotor activity in open field test (OFT). 1-amine as a potent inhibitor for the dopamine and serotonin transporters. They showed that compounds (7) and (8) have H N strong binding affinity to DAT and SERT (3.83 and 0.815 COOCH3 O nM respectively) and a 1000-fold selectivity compared to the H NH Norepinephrine transporter (NET) binding affinity. O (1) H S N NH Bispyridyl ethers have indoline nucleus and have selected or HN H N potent activity towards CNS disorder. (SB-242084) and (SB- Cl 243213) (Phase 1 clinical trials) are bispyridyl ethers having (7) Cl (8) potent 5-HT2C receptor inverse agonistic activity and selective Serotonergic neurotransmission is known to modulate various activity for both the 5-HT2A and 5-HT2B receptors. Bromidge physiological and behavioral functions in the CNS. It is related [14] et al., synthesized a series of bisaryl ethers and evaluated their to ‘integrating’ emotion, cognition, motor function, pain, antidepressant activity. Compounds (2), (3) and (4) possess circadian rhythm and neuroendocrine functions. Ben-Daniel et potent activity in the rat hypolocomotion assay. al.,[9] synthesized a new class of indole derivatives, some potent compounds have low nanomolar affinity for the SERT and high H H H N O N O N O selectivity for 5-HT1A receptor. Six indolylpropylamine derivatives N N N N N N N O N O N O N Cl Cl were synthesized and evaluated for SERT inhibitory activity. CH3 CH3 (2) (3) (4) The most potent compound (9), 2-[3-(5-fluoro-1H-indol-3- CF3 CH3 Me yl)-propyl]-6-methoxy-1,2,3,4-tetrahydro isoquinoline showed promising antidepressant effect and was also evaluated in vivo Shelke et al.,[15] synthesized a series of 2-(5H-[1,2,4] triazino using positron emission tomography (PET) in animal models. [5,6-b]indol-3-ylthio)-N-(substituted phenyl) acetamides. Selected compounds were screened for potential antidepressant F activity on animal model by tail suspension test (TST) in mice. On the basis of quantitative structure activity relationship (QSAR) study they proved that compounds like (5a), (5n), (5o), N (5j) and (5p) have activity compared to standard antidepressant HN (9) O drugs moclobemide, imipramine and fluoxetine. Journal of Pharmacy and Bioallied Sciences April-June 2011 Vol 3 Issue 2 195 Siddique, et al.: Antidepressant potential of nitrogen containing heterocyclic moieties: An updated review Table 1: Survey of the pharmacological mechanisms of new accepted antidepressants in clinical development[8] Target/mechanism Compound Phase Company Monoamine transporter SERT, NET Desmethylvenlafaxine III Wyeth SERT, NET, DAT DOV216303 II DOV Pharmaceuticals NS-2359 II NeuroSearch, GSK DOV21947 I DOV Pharmaceuticals SEP-225289 I Sepracor SERT+ SERT, 5-HT1A agonist Vilazodone II Genaissance SERT, several 5-HT receptors AA21004 II Lundbeck Monoamine receptors 5-HT1A agonist Osemozotan