Synthesis of novel 5-substituted-2-aminotetralin analogs: 5-HT and 5-HT G protein-coupled receptor affinity, 3D-QSAR and molecular modeling.

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.

Concepts Keywords
3D Free energy calculations
Affinity Neurodevelopmental neuropsychiatric disorders
Amine Symptoms autism
Analog Branches of biology
Autism Chemical compounds
Chiral Organic compounds
Clinical Translation Serotonin receptors
Free Energy Indoles
GPCR Biomolecules
Homologous Cell signaling
Homology Modeling Ligand
Hydrophobic Proteins
Ligands 5-HT2A receptor
Molecular Dynamics Naphthylpiperazine
Molecular Modeling Molecular modeling
Receptor Affinity


Type Source Name
drug DRUGBANK Serotonin
disease MESH autism

Original Article

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