Publication date: Feb 01, 2020
The serotonin 5-HT 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-HT. 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-HT GPCR, and can treat symptoms of autism in mouse models; subsequently, the lead was found to have high affinity at the 5-HT 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-HT receptor for comparison with similar studies at the highly homologous 5-HT receptor. We report 35 new 5-SAT ligands, some with very high affinity (K ? 1 nM) and stereoselectivity at 5-HT + or 5-HT receptors, several with modest selectivity (up to 12-fold) for binding at 5-HT, and, several ligands with high selectivity (up to 40-fold) at the 5-HT receptor. 3D-QSAR results indicate that steric extensions at the C(5)-position improve selectivity for the 5-HT over 5-HT receptor, while steric and hydrophobic extensions at the chiral C(2)-amino position impart 5-HT 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-HT vs. 5-HT GPCRs, as may be required for successful clinical translation.
Perry, C.K., Casey, A.B., Felsing, D.E., Vemula, R., Zaka, M., Herrington, N.B., Cui, M., Kellogg, G.E., Canal, C.E., and Booth, R.G. Synthesis of novel 5-substituted-2-aminotetralin analogs: 5-HT and 5-HT G protein-coupled receptor affinity, 3D-QSAR and molecular modeling. 15143. 2020 Bioorg Med Chem (28):3.