Patent Highlight Cite This: ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
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Allosteric CB1 Receptor Modulators for the Treatment of CB1 Related Diseases and Conditions Robert B. Kargbo* Usona Institute, 277 Granada Drive, San Luis Obispo, California 93401-7337, United States
ACS Med. Chem. Lett. Downloaded from pubs.acs.org by 91.204.14.230 on 12/04/18. For personal use only.
Important Compound Classes.
which was initially developed for obesity, was withdrawn from the market due to risk of suicidal ideation and psychiatric side effects. In addition, licensed cannabinoid medications that contain THC are prescribed with many restrictions due to the possibility of psychoactivity and additive tendency. However, the CB2 receptor is found mainly in immune cells and modulate cytokine release and immune cell migration. The CB2 receptor has similarity in amino acid sequence to the CB1 receptor, and its discovery helped explained the pharmacological properties of tetrahydrocannabinol and the effects of cannabinoids on the immune system. CB2 receptors inhibit the activity of adenylyl cyclase through their Gi/Goα subunits and are also known to couple to the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway (MAPK-ERK pathway). Selective CB2 agonists are therapeutics for treatment of CB2-receptor expressing malignant gliomas, multiple sclerosis, tumors of immune origin, osteoporosis, and so forth. Growing evidence suggests that the CB1 receptor exists in multiple active conformations, each of which may display an alternate approach in regulating unique signaling pathways. Recently, several small molecules have been identified as allosteric modulators of the CB1 receptor that bind to distinct binding sites from the orthosteric site. Compared to orthosteric ligands, allosteric modulators offer many therapeutic advantages, such as minimal evolutionary burden, and allosteric binding pockets have amino acid sequences that are not highly conserved and may be more specific for each receptor subtype. In addition, allosteric modulators have a ceiling effect due to their limited allosteric cooperativity, which can be used to generate titrated pharmacological responses and also to fine-tune endogenous signaling without affecting the spatial and temporal aspects of endogenous signaling. Furthermore, the different receptor conformation states induced by allosteric modulators can be biased for coupling to different G proteins or β-arrestin. Thus, these attributes can impact intracellular signaling pathways and offer promising avenues to develop subtype-specific and pathway-specific therapeutics. Examples of allosteric modulators that have advanced to the market, include Cinacalcet, a positive allosteric modulator (PAM), and Maraviroc, a negative allosteric modulator (NAM). The compounds of this Patent Highlight are novel cannabinoid CB1 receptor allosteric modulators that can be useful in the treatment of diseases and conditions caused by physiological processes implicating the cannabinoid CB1 receptor. These include drug dependence, learning disorder, pain regulation, appetite control, cardiovascular regulation, and memory and metabolic syndromes.
Title. Diarylureas as CB1 Allosteric Modulators Patent Application Number. WO 2018/209030 A1 Publication Date. November 15, 2018 Priority Application. US 62/505,383 Priority Date. May 12, 2017 Inventors. Zhang, Y.; Nguyen, T.; German, N. Assignee Company. RTI International. Disease Area. Cardiovascular and Metabolic Diseases Biological Target. CB1 Receptor Summary. The endocannabinoid system (ECS) consists of two well characterized receptor subtypes, the cannabinoid receptor 1 (CB1) and the cannabinoid receptor 2 (CB2). They are endogenous lipid-based retrograde neurotransmitters that binds to cannabinoid receptors and are activated by the psychoactive component of marijuana (Cannabis sativa) Δ9-tetrahydrocannabinol (THC). In addition, both receptors belong to a class 1A rhodopsin-like cell membrane receptors in the G protein-coupled receptor (GPCR) superfamily. There are growing evidence that the ECS is involved in a number of physiological processes and pathologies, including cancer, metabolic and eating disorders, neurodegeneration, locomotion, pain, liver disease, and immunosuppression. Thus, the ECS provide excellent options for the development of new drugs. The CB1 receptors are one of the most abundant GPCRs expressed in the central nervous system and are also present at much lower concentrations in the spleen, tonsil, arteries, bone marrow, lungs, heart, and so forth. They attenuate a wide variety of physiological functions such as cardiovascular, respiratory, metabolism, neuronal development, cell proliferation, and apoptosis. Upon activation, the CB1 receptor primarily couples to Gi/o-type G proteins, which leads to downstream inhibition of adenylyl-cyclase and reduces cAMP levels in cells. Furthermore, CB1 receptor can negatively couple to N- and P/Q-type voltage-gated Ca2+ channels and positively couple to A-type and inwardly rectifying K+ channels. Because of its complex signaling network, CB1 has been demonstrated as a viable target in the pathology of many disorders and thus is a promising therapeutic target for ameliorating diseases including drug addition, multiple sclerosis, psychosis, nausea, obesity, neurodegenerative disorders, pain, gastrointestinal diseases, and inflammation. Consequently, extensive efforts have been invested to generate cannabinoid-based therapeutics; however, only a few medications from cannabinergic compounds are commercially available due to the extensive side effects associated with CB1 orthosteric ligands. For example, rimonabant, a CB1 ligand, © XXXX American Chemical Society
Received: November 24, 2018
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DOI: 10.1021/acsmedchemlett.8b00575 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
Patent Highlight
Definitions. R1 = O−(C1−6 alkyl), O−(5− to 13−membered cycloalkyl), N(R2)2, NO2, halogen, and so forth. R2 = H, C1−6 alkyl, C1−6 alkenyl, C1−6 alkynyl, 5- to 13-membered aryl. R3 = H, C1−6 alkyl, C1−6 alkenyl, C1−6 alkynyl, halogen, NO2, CN. N = 1, 2, or 3. Key Structures.
Recent Review Articles. 1. Piazza, P. V.; Cota, D.; Marsicano, G. Neuron. 2017, 93, 1252. 2. Nguyen, T.; Li, J. X.; Thomas, B. F.; Wiley, J. L.; Kenakin, T. P.; Zhang, Y. Med. Res. Rev. 2017, 37, 441. 3. Oliveira da Cruz, J. F.; Robin, L. M.; Drago, F.; Marsicano, G.; Metna-Laurent, M. Neuroscience. 2016, 323, 35. 4. Battista, N.; Di Tommaso, M.; Bari, M.; Maccarrone, M. Front. Behav. Neurosci. 2012, 6, 1−7.
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AUTHOR INFORMATION
Corresponding Author
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[email protected]. ORCID
Robert B. Kargbo: 0000-0002-5539-6343 Notes
The author declares no competing financial interest.
Biological Assay. The FLIPR-based calcium mobilization assays were used as the primary screen to assess the potency at the CB1 and CB2 receptors. The compounds were also evaluated in antagonizing agonist-stimulated [35S]GTP-γ-S binding to CB1 receptor. Metabolic stability assessment was carried out for some test compounds and also the reinstatement of extinguished cocaine-seeking behavior using adult male Sprague−Dawley rats. Biological Data. The Table below shows allosteric modulatory activities of compounds in this Patent Highlight in the CB1 calcium mobilization assay and [35S]GTP-γ-S binding assay. Substantial metabolic stability was reported for compound 34 (T1/2 = 300 min, CL =
