Faculty Fellow Center for Drug Discover
Office: 145 The Fenway
BS in Chemistry from University of Mumbai
MS in Chemistry from IIT Mumbai
PhD in Organic Chemistry from Institute of Chemical Technology, Mumbai
Chemistry; Medicinal Chemistry
Research Interests:The endocannabinoid system which is comprised of two cannabinoid receptors, endogenous cannabinoids and several proteins and enzymes involved in their biosynthesis, transport and bioinactivation, has been implicated in multiple regulatory functions both in health and disease. D9-Tetrahydrocannabinol (D9-THC), the major psychoactive constituent of marijuana (Cannabis Sativa L.) produces its physiological and psychological effects by interaction with two cannabinoid receptors: CB1 receptors, which are mainly located in the central nervous system, and CB2 receptors which are found mainly in peripheral tissues, such as spleen, tonsils and immunocytes. The adverse CNS side effects of D9-THC are mainly mediated by brain CB1 receptors. The CB2 subtype is of particular interest since it has been identified as a potential target for immune- modulator therapies and CB2 selective agonists have potential utility in the treatment of peripheral and neuropathic pain and inflammation without any undesirable CB1 mediated CNS side effects. The clinical utility of several CB subtype selective as well as CB1/CB2 mixed agonists in treating pain, glaucoma, depression and GI disorders have been demonstrated preclinically. Our current efforts are focused on developing CB2 selective agonists as well as peripherally restricted CB1/CB2 agonists.
Several GPCRs have been shown to contain allosteric binding sites for endogenous/synthetic ligands which are discrete from the agonist binding (orthosteric) site. The binding of allosteric modulators leads to a conformational change of the receptor which affects the affinity and/or efficacy of the orthosteric (endogenous) ligands, thereby fine-tuning its actions. Potential advantages of CB1-receptor allosteric inhibitors, and very recently discovered functional enhancers, include greater receptor subtype selectivity and reduced side effects. An important component of our research work, which is funded by NIH, is focused on developing novel CB1 selective allosteric modulators which include both positive allosteric modulator (PAM) and negative allosteric modulator (NAM).
The extensive physiological influence of transmission through the CB receptors makes these GPCRs promising therapeutic targets for treating several pathophysiological conditions. However, there is little direct structural information pertaining to both CB1 and CB2 receptor ligand recognition and activation. In the absence of the crystal structures of these cannabinoid receptors, we have successfully gained such information for orthosteric site of both CB1 and CB2 receptors using an in-house developed experimental approach termed as “ligand-assisted protein structure” (LAPS). We are currently utilizing this approach to characterize the allosteric site(s) of CB1 receptor.
Courses:PHSC4501 (Fall Semester): Pharmacology and Medicinal Chemistry I PHSC4502 (Summer Semester): Pharmacology and Medicinal Chemistry II
1. Dixon, D.D., Sethumadhavan, D., Benneche, T., Banaag, A.R., Tius, M.A., Thakur, G.A., Bowman, A., Wood, J., Makriyannis, A. Heteroadamantyl Cannabinoids. J. Med. Chem., 2010, 53(15), 5656-66.
2. Thakur, G. A٭. , Tichkule, R., Bajaj, S., Makriyannis, A., Recent advances in cannabinoid receptor agonist. Expert Opinion on Therapeutic Patents. 2009, 19 (12), 1647-73.
3. Pei, Y., Mercier, R.W., Anday, J.K., Thakur, G.A., Zvonok, A.M., Reggio, P.H., Janero, D.R., Makriyannis, A., (2008), Ligand-binding architecture of human CB2 cannabinoid receptor: evidence for a receptor subtype-specific binding motif and modeling GPCR activation. Chem. Biol., 15(11), 1207-19.
4. Rahn, E.J., Zvonok, A.M., Thakur, G.A., Khanolkar, A.D., Makriyannis, A., Hohmann, A.G., (2008), Selective activation of cannabinoid CB2 receptors suppresses neuropathic nociception induced by treatment with the chemotherapeutic agent paclitaxel in rats. JPET., 327(2), 584-91.
5. Nikas, S.P., Thakur, G.A., Parrish, D.A., Alapafuja, S.O., Huestis, M., Makriyannis, A., (2007), A concise methodology for the synthesis of (−)D9-tetrahydrocannabinol and (−)D9-tetrahydrocannabivarin metabolites and their regiospecifically deuterated analogs. Tetrahedron, 63, 8112-8123.
6. Khanolkar, A.D., Lu, D., Ibrahim, M., Duclos, R.I. Jr., Thakur, G.A., Malan, T.P. Jr., Porreca, F., Veerappan, V., Tian, X., George, C., Parrish, D.A., Papahatjis, D.P., Makriyannis, A., (2007), Cannabilactones: a novel class of CB2 selective agonists with peripheral analgesic activity. J. Med. Chem., 50 (26), 6493-6500.
7. Thakur, G.A., Nikas,S.P., Duclos, R.,I.,Jr., Makriyannis, A., (2005), Methods for the synthesis of cannabinergic ligands. Methods Mol. Med., 123, 113-148.
8. Lu, D., Meng, Z., Thakur, G.A., Fan, P., Steed, J., Tartal, C.L., Hurst, D.P., Reggio, P,H., Deschamps, J.R., Parrish, D.A., George, C., Jarbe, T.U., Lamb, R.J., Makriyannis, A., (2005), Adamantyl Cannabinoids: A novel class of cannabinergic ligands. J. Med. Chem., 48 (14), 4576-4585
9. Thakur, G.A., Nikas, S.P., Li, C., Makriyannis, A., (2005), Structural requirements for cannabinoid receptor probes. Handbook of Experimental Pharmacology, 168, 209-246.
10. Picone, R.P., Khanolkar, A.D., Xu, W., Ayotte L.A., Thakur, G.A., Hurst, D.P., Abood, M.E., Reggio, P.H., Fourier, D.J., Makriyannis, A., (2005), (-)-7′-Isothiocyanato-11-hydroxy-1′,1′-dimethylheptylhexahydrocannabinol (AM841), a high-affinity electrophilic ligand, interacts covalently with a cysteine in helix six and activates the CB1 cannabinoid receptor. Mol. Pharmacol., 68 (6), 1623-1635
11. Thakur, G.A., Palmer, S., Harrington, P.E., Stergiades, I.A., Tius, M.A., Makriyannis, A., (2002), Enantiomeric resolution of a novel chiral cannabinoid receptor ligand. J. Biochem. Biophys. Methods, 54(1-3), 415-422