Allosteric modulators of the serotonin (5-HT) 5-HT2C receptor (5-HT2CR) present a unique drug design strategy to augment the response to endogenous 5-HT in a site- and event-specific manner with great potential as novel central nervous system probes and therapeutics. To date, there is only one reported 5-HT2CR allosteric modulator, PNU-69176E. By using the scaffold of this lead compound and employing homology modeling via molecular docking techniques, a series of new small molecules such as CYD-1-79, CYD-6-10-2, and CYD-6-16-2 have been rationally designed and synthesized. Their pharmacological activities have been evaluated using a battery of in vitro functional and radioligand binding assays as well as in vivo behavioral studies to assess allosteric modulation of the 5-HT2CR. CYD-1-79 with a simplified polar head was found to enhance 5-HT2CR-mediated Cai++ release and ERK1/2 activation induced by the endogenous ligand 5-HT or the selective 5-HT2CR agonist WAY 163909. It also exhibited a favorable overall PK profile such as oral bioavailability (F = 39.1%) and half-life (t1/2 = ~6 hr). More importantly, the in vivo efficacy of the new 5-HT2CR positive allosteric modulator CYD-1-79 was well demonstrated in our preliminary rodent behavior studies (e.g., spontaneous locomotor activity, self-grooming, impulsive action). Taken together, our target-based drug design and development efforts on 5-HT2CR allosteric modulators open new avenues in probing the 5-HT2CR function and discovering novel pharmacotherapeutics for CNS disorders including addictions and impulse control disorders.

Design, synthesis, and pharmacological evaluation of novel positive allosteric modulators (PAMs) of 5-HT<sub>2C </sub>?receptor

247th National Meeting (2014)

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Design, synthesis, and pharmacological evaluation of novel positive allosteric modulators (PAMs) of 5-HT2C ?receptor

Design, synthesis, and pharmacological evaluation of novel positive allosteric modulators (PAMs) of 5-HT_2C?receptor