Thakur Lab
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My research interests are focused on developing novel medications for the treatment of drug addiction, neuropathic pain, eating disorders and cognition and memory deficits associated with Alzheimer’s disease and Schizophrenia. Our drug targets include: CB1/CB2 receptors, alpha7 nAChR and nNOS-PSD95.

Targeting Cannabinoid Receptors for the Treatment of Pain and GI Disorders
delta9-Tetrahydrocannabinol (delta 9-THC), the major psychoactive constituent of marijuana (Cannabis Sativa L.) produces its physiological effects by interaction with cannabinoid receptors (CB1 and CB2). Cannabinoid receptors influence diverse cellular signal-transduction pathways. CB1 receptors are mainly located in the central nervous system, whereas the CB2 receptors are found mainly in peripheral tissues, such as spleen, tonsils and immunocytes. The adverse CNS side effects of delta 9-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. Several CB selective and CB1/CB2 mixed agonists have demonstrated preclinically potential clinical utility in treating pain, glaucoma, depression and GI disorders. CB2 selective agonists have potential utility in the treatment of peripheral and neuropathic pain and inflammation without any undesirable CB1 mediated CNS side effects which include dizziness, dry mouth, tiredness/fatigue, muscle pain and palpitations. Current CB1 direct-acting ligand development project includes: 1) Development of CB1 selective and water-soluble cannabinoids 2) Development of CB2 selective cannabinoids 3) Development of peripherally-restricted cannabinoids

A. Mapping the Binding-Sites of Cannabinoid Receptors (both Orthosteric and Allosteric sites):
In order to improve the selectivity of CB-receptor ligands with an eye towards their therapeutic use, the three-dimensional structure of CB receptors (and virtually all other GPCRs) needs to be characterized. In the absence of experimentally determined structures of cannabinoid receptors, information about their ligand-binding sites may best be obtained through the use of affinity probes coupled with mass spectrometric analysis of labeled protein. This project involves design and synthesis of: 1) Covalent and electrophilic probes 2) “Click-chemistry” probes Currently, my laboratory has developed key covalent probes for CB1 allosteric probes that have been characterized in functional assays are being currently evaluated in receptor labeling studies.

B. Allosteric Modulators of CB1 Cannabinoid Receptors
Recent discovery of an allosteric binding site on the cannabinoid CB1 receptor invites new approaches to potential drugs that modulate cannabinoid signaling for therapeutic benefit. 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 which affects the affinity and/or efficacy of the orthosteric (endogenous) ligands, thereby fine-tuning its actions. Putative advantages of CB1-receptor allosteric inhibitors, and very recently discovered functional enhancers, include greater receptor subtype selectivity and reduced side effects. My 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). We have developed some potent and functionally selective allosteric modulators which are well-characterized in vitro and in vivo. Our current finding shows that CB1 PAMs may provide all or most of the beneficial effects of CB1 activation but are devoid of CB1 agonist related side effects. We hope that this work together with the allosteric covalent probe/LAPS studies will contribute significantly towards the understanding of structural requirements of the CB1 receptor’s allosteric binding site and facilitate the development of preclinical candidates. The most potent CB1 PAMs are being studied for treatment of Glaucoma, PTSD, Neuropathic Pain and Anorexia Nervosa in animal models.

C. Development of Inhibitors of nNOS-PSD95 protein-protein interaction: We have recently initiated our efforts on developing novel inhibitors of nNOS-PSD95 protein-protein interactions for the treatment of neuropathic pain, drug addiction and PTSD. Two key ligands GAT404 and GAT405 have been shown to be more potent than literature established tools and are being currently further evaluated.

D. Development of Selective and Potent Allosteric Modulators of 7 Nicotinic Acetylcholine Receptors: Nicotinic acetylcholine receptors (nAChR), members of Cys-loop superfamily of cationic ligand-gated ion channels are involved in the physiological responses to the neurotransmitter acetylcholine (ACh) and are distributed throughout the central and peripheral nervous systems. The alpha7 nAChRs are expressed at high levels in areas involved with learning and memory and play pivotal roles in modulating neurotransmission in these area. It has been considered a promising target for improving cognitive impairments in diseases such as Alzheimer’s (AD) and schizophrenia as well as for treatment of inflammation and neuropathic pain. So far our laboratory has developed potent 7 nAChR PAMs and ago-PAMs and the lead molecule GAT107 shown good potency in improving memory and cognition in animal models as well as reducing pain in animal models of neuropathic pain.