Shashikanth Ponnala1, Nirav Kapadia2, Sudharshan Madapa1, Ian L Alberts3, Wayne W Harding4. 1. Hunter College, City University of New York, Department of Chemistry, 695 Park Avenue, NY 10065, USA. 2. Hunter College, City University of New York, Department of Chemistry, 695 Park Avenue, NY 10065, USA; The Graduate Center, City University of New York, 365 5th Avenue, New York, NY 10016, USA. 3. LaGuardia Community College, Department of Chemistry, 31-10 Thompson Avenue, LIC, NY 11104, USA. 4. Hunter College, City University of New York, Department of Chemistry, 695 Park Avenue, NY 10065, USA; The Graduate Center, City University of New York, 365 5th Avenue, New York, NY 10016, USA. Electronic address: whardi@hunter.cuny.edu.
Abstract
A series of C1 aporphine analogs related to compound 5 and that contain substituted allylic, alkynyl, nitrile, ester and benzyl groups was synthesized and evaluated for affinity at h5HT2A and α1A receptors in functional activity assays that measure calcium release. The presence of branched allylic substituent groups diminished affinity for the h5HT2A receptor. Likewise, the alkynyl, nitrile and ester derivatives evaluated displayed lower 5-HT2A receptor affinity as compared to 5. Hydrophobic, steric and electronic effects impact the affinity of p-substituted benzyl derivatives 8i-8k but in different ways. High hydrophobicity and size favor 5-HT2A affinity whereas, high electronegativity disfavors 5-HT2A affinity. p-Bromobenzyl analog 8k was identified as a 5-HT2A receptor selective ligand, with the highest 5-HT2A receptor affinity of any aporphine known to date. Most of the other analogs were selective for the 5-HT2A versus the α1A receptor. ChemScore binding energies from docking studies correlated qualitatively with the observed trends in affinity for 8i-8k, although the binding energies were not well differentiated quantitatively.
A series of C1 aporphine analogs related to compound 5 and that contain substituted allylic, n class="Chemical">alkynyl, nitrile, ester and benzyl groups was synthesized and evaluated for affinity at h5HT2A and α1A receptors in functional activity assays that measure calcium release. The presence of branched allylic substituent groups diminished affinity for the h5HT2A receptor. Likewise, the alkynyl, nitrile and ester derivatives evaluated displayed lower 5-HT2A receptor affinity as compared to 5. Hydrophobic, steric and electronic effects impact the affinity of p-substituted benzyl derivatives 8i-8k but in different ways. High hydrophobicity and size favor 5-HT2A affinity whereas, high electronegativity disfavors 5-HT2A affinity. p-Bromobenzyl analog 8k was identified as a 5-HT2A receptor selective ligand, with the highest 5-HT2A receptor affinity of any aporphine known to date. Most of the other analogs were selective for the 5-HT2A versus the α1A receptor. ChemScore binding energies from docking studies correlated qualitatively with the observed trends in affinity for 8i-8k, although the binding energies were not well differentiated quantitatively.
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