1. Synthesis and Structure-Activity Relationships of 2,5-Dimethoxy-4-Substituted Phenethylamines and the Discovery of CYB210010: A Potent, Orally Bioavailable and Long-Acting Serotonin 5-HT 2 Receptor Agonist.
- Author
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Varty GB, Canal CE, Mueller TA, Hartsel JA, Tyagi R, Avery K, Morgan ME, Reichelt AC, Pathare P, Stang E, Palfreyman MG, and Nivorozhkin A
- Subjects
- Structure-Activity Relationship, Animals, Humans, Administration, Oral, Male, Biological Availability, Rats, Mice, Rats, Sprague-Dawley, Drug Discovery, Receptors, Serotonin, 5-HT2 metabolism, Receptor, Serotonin, 5-HT2A metabolism, Phenethylamines pharmacology, Phenethylamines chemistry, Phenethylamines chemical synthesis, Serotonin 5-HT2 Receptor Agonists pharmacology, Serotonin 5-HT2 Receptor Agonists chemistry, Serotonin 5-HT2 Receptor Agonists chemical synthesis
- Abstract
Structure-activity studies of 4-substituted-2,5-dimethoxyphenethylamines led to the discovery of 2,5-dimethoxy-4-thiotrifluoromethylphenethylamines, including CYB210010, a potent and long-acting serotonin 5-HT
2 receptor agonist. CYB210010 exhibited high agonist potency at 5-HT2A and 5-HT2C receptors, modest selectivity over 5-HT2B , 5-HT1A , 5-HT6 , and adrenergic α2A receptors, and lacked activity at monoamine transporters and over 70 other proteins. CYB210010 (0.1-3 mg/kg) elicited a head-twitch response (HTR) and could be administered subchronically at threshold doses without behavioral tolerance. CYB210010 was orally bioavailable in three species, readily and preferentially crossed into the CNS, engaged frontal cortex 5-HT2A receptors, and increased the expression of genes involved in neuroplasticity in the frontal cortex. CYB210010 represents a new tool molecule for investigating the therapeutic potential of 5-HT2 receptor activation. In addition, several other compounds with high 5-HT2A receptor potency, yet with little or no HTR activity, were discovered, providing the groundwork for the development of nonpsychedelic 5-HT2A receptor ligands.- Published
- 2024
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