Structural manipulation of aporphines via C10 nitrogenation leads to the identification of new 5-HT7AR ligands |
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| Institution: | 1. Department of Chemistry, Hunter College, City University of New York, 695 Park Avenue, NY 10065, USA;3. LaGuardia Community College, Department of Chemistry, 31-10 Thompson Avenue, LIC, NY 11104, USA;1. Department of Chemistry, University of Houston, College of Natural Sciences and Mathematics, Houston, TX 77204, United States;2. Department of Pharmacological and Pharmaceutical Sciences, University of Houston, College of Pharmacy, Houston, TX 77204, United States;1. Department of Chemistry, Hunter College, City University of New York, 695 Park Avenue, New York 10065, USA;2. Ph.D. Program in Chemistry, The Graduate Center of The City University of New York, 365 5th Avenue, New York 10016, USA;3. Molecular Design Institute, Department of Chemistry, New York University, 100 Washington Square, New York 10003, USA;4. Ph.D. Program in Biochemistry, The Graduate Center of The City University of New York, 365 5th Avenue, New York 10016, USA;1. Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA;2. Department of Pharmacy, University of Chieti-Pescara “G. d’Annunzio”, Chieti, 66100 Italy;3. Department of Pharmacology, University of Arizona, Tucson, AZ 85724, USA;1. Department of Chemistry, Hunter College, City University of New York, 695 Park Avenue, NY 10065, USA;3. LaGuardia Community College, Department of Chemistry, 31-10 Thompson Avenue, LIC, NY 11104, USA;1. Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK;2. Programa de Pós-Graduação em Medicina Tropical do Instituto de Medicina Tropical da Universidade de São Paulo, Av. Dr. Eneas de Carvalho Aguiar 470, 05403-000, São Paulo, Brazil;3. Centre for Parasitology and Mycology, Instituto Adolfo Lutz, Av. Dr. Arnaldo 351, 01246-000, São Paulo, Brazil;1. Division of Basic Neuroscience, Medicinal Chemistry Program, McLean Hospital, Belmont, MA 02478, United States;2. Department of Psychiatry, Harvard Medical School, Boston, MA 02115, United States |
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| Abstract: | Aporphine alkaloids containing a C10 nitrogen motif were synthesized and evaluated for affinity at 5-HT1AR, 5-HT2AR, 5-HT6R and 5-HT7AR. Three series of racemic aporphines were investigated: 1,2,10-trisubstituted, C10 N-monosubstituted and compounds containing a C10 benzofused aminothiazole moiety. The 1,2,10-trisubstituted series of compounds as a group displayed modest selectivity for 5-HT7AR and also had moderate 5-HT7AR affinity. Compounds from the C10 N-monosubstituted series generally lacked affinity for 5-HT2AR and 5-HT6R and showed strong affinity for 5-HT1A or 5-HT7AR. Compounds in this series that contained an N6-methyl group were up to 27-fold selective for 5-HT7AR over 5-HT1AR, whereas compounds with an N6-propyl substituent showed a reversal in this selectivity. The C10 benzofused aminothiazole analogues showed a similar binding profile as the C10 N-monosubstituted series i.e. strong affinity for 5-HT1AR or 5-HT7AR, with selectivity between the two receptors being similarly influenced by N6-methyl or N6-propyl substituents. Compounds 29 and 34a exhibit high 5-HT7AR affinity, excellent selectivity versus dopamine receptors and function as antagonists in 5-HT7AR cAMP-based assays. Compounds 29 and 34a have been identified as new lead molecules for further tool and pharmaceutical optimization. |
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| Keywords: | Aporphine Serotonin Dopamine CNS SAR |
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