Synthesis of novel 5-substituted-2-aminotetralin analogs: 5-HT1A and 5-HT7 G protein-coupled receptor affinity, 3D-QSAR and molecular modeling |
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| Affiliation: | 1. Center for Drug Discovery, Department of Pharmaceutical Sciences, Department of Chemistry & Chemical Biology, Northeastern University, Boston, MA 02115, USA;2. Department of Medicinal Chemistry & Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA 23298, USA;1. Science Department, Dominican College, 470 Western Highway, Orangeburg, NY 10962, USA;2. Department of Chemistry, Small Molecule X-ray Crystallography Facility, Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD 21218, USA;1. Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodźki St., PL-20093, Lublin, Poland;2. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark;3. Department of Pharmacology, Universidade de Santiago de Compostela, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Avda de Barcelona, Santiago de Compostela, E-15782, Spain;4. Department of Pharmacology and Pharmacodynamics, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodźki St., PL-20093, Lublin, Poland;5. Department of General and Coordination Chemistry, Maria Curie-Skłodowska University, M. Curie-Skłodowskiej Sq. 2, PL-20031, Lublin, Poland;6. School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, P.O. Box 1627, FI-70211, Kuopio, Finland;1. Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, 23298, USA;2. The Institute for Structural Biology, Drug Discovery and Development School of Pharmacy, Virginia Commonwealth University, Richmond, VA, 23298, USA;1. Centre for Data Engineering and Computational Modeling, Indian Institute of Information Technology and Management-Kerala, India;2. Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute & Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, USA;1. Jagiellonian University Medical College, Faculty of Pharmacy, Department of Medicinal Chemistry, 9 Medyczna Street, 30-688, Kraków, Poland;2. Polish Academy of Sciences, Maj Institute of Pharmacology, Department of Medicinal Chemistry, 12 Smętna Street, 31-343, Kraków, Poland;3. Jagiellonian University Medical College, Faculty of Pharmacy, Department of Pharmacobiology, 9 Medyczna Street, 30-688, Kraków, Poland;4. Jagiellonian University Medical College, Faculty of Pharmacy, Department of Pharmacokinetics and Physical Pharmacy, 9 Medyczna Street, 30-688, Kraków, Poland;5. Jagiellonian University Medical College, Faculty of Pharmacy, Department of Clinical Pharmacy, 9 Medyczna Street, 30-688, Kraków, Poland;6. Jagiellonian University Medical College, Faculty of Pharmacy, Department of Technology and Biotechnology of Drugs, Medyczna 9, 30-688, Kraków, Poland |
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| Abstract: | The serotonin 5-HT7 G protein-coupled receptor (GPCR) is a proposed pharmacotherapeutic target for a variety of central and peripheral indications, albeit, there are no approved drugs selective for binding 5-HT7. We previously reported that a lead analog based on the 5-substituted-N,N-disubstituted-1,2,3,4-tetrahydronaphthalen-2-amine (5-substituted-2-aminotetralin, 5-SAT) scaffold binds with high affinity at the 5-HT7 GPCR, and can treat symptoms of autism in mouse models; subsequently, the lead was found to have high affinity at the 5-HT1A GPCR. Herein, we report the synthesis of novel 5-SAT analogs to develop a 3-dimensional quantitative structure—affinity relationship (3D-QSAR) at the human 5-HT7 receptor for comparison with similar studies at the highly homologous 5-HT1A receptor. We report 35 new 5-SAT ligands, some with very high affinity (Ki ≤ 1 nM) and stereoselectivity at 5-HT7 + or 5-HT1A receptors, several with modest selectivity (up to 12-fold) for binding at 5-HT7, and, several ligands with high selectivity (up to 40-fold) at the 5-HT1A receptor. 3D-QSAR results indicate that steric extensions at the C(5)-position improve selectivity for the 5-HT7 over 5-HT1A receptor, while steric and hydrophobic extensions at the chiral C(2)-amino position impart 5-HT1A selectivity. In silico receptor homology modeling studies, supplemented with molecular dynamics simulations and binding free energy calculations, were used to rationalize experimentally-determined receptor selectivity and stereoselective affinity results. The data from these studies indicate that the 5-SAT chemotype, previously shown to be safe and efficacious in rodent paradigms of neurodevelopmental and neuropsychiatric disorders, is amenable to structural modification to optimize affinity at serotonin 5-HT7 vs. 5-HT1A GPCRs, as may be required for successful clinical translation. |
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| Keywords: | Serotonergic receptor 2-aminotetralin 3D-QSAR Molecular modeling |
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