1. Utilization of an Active Site Mutant Receptor for the Identification of Potent and Selective Atypical 5-HT 2C Receptor Agonists.
- Author
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Carpenter J, Wang Y, Wu G, Feng J, Ye XY, Morales CL, Broekema M, Rossi KA, Miller KJ, Murphy BJ, Wu G, Malmstrom SE, Azzara AV, Sher PM, Fevig JM, Alt A, Bertekap RL Jr, Cullen MJ, Harper TM, Foster K, Luk E, Xiang Q, Grubb MF, Robl JA, and Wacker DA
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 genetics, ATP Binding Cassette Transporter, Subfamily G, Member 2 genetics, Animals, Arginine chemical synthesis, Arginine chemistry, Arginine pharmacology, Brain metabolism, Caco-2 Cells, Cell Membrane Permeability, Feeding Behavior drug effects, Flavones chemical synthesis, Flavones pharmacology, HEK293 Cells, Humans, Male, Membranes, Artificial, Mice, Knockout, Microsomes, Liver metabolism, Mutation, Rats, Sprague-Dawley, Receptor, Serotonin, 5-HT2A metabolism, Receptor, Serotonin, 5-HT2B metabolism, Receptor, Serotonin, 5-HT2C genetics, Serotonin 5-HT2 Receptor Agonists chemical synthesis, Serotonin 5-HT2 Receptor Agonists pharmacokinetics, Serotonin 5-HT2 Receptor Agonists pharmacology, Structure-Activity Relationship, Arginine analogs & derivatives, Flavones chemistry, Receptor, Serotonin, 5-HT2C metabolism, Serotonin 5-HT2 Receptor Agonists chemistry
- Abstract
Agonism of the 5-HT
2C receptor represents one of the most well-studied and clinically proven mechanisms for pharmacological weight reduction. Selectivity over the closely related 5-HT2A and 5-HT2B receptors is critical as their activation has been shown to lead to undesirable side effects and major safety concerns. In this communication, we report the development of a new screening paradigm that utilizes an active site mutant D134A (D3.32) 5-HT2C receptor to identify atypical agonist structures. We additionally report the discovery and optimization of a novel class of nonbasic heterocyclic amide agonists of 5-HT2C . SAR investigations around the screening hits provided a diverse set of potent agonists at 5-HT2C with high selectivity over the related 5-HT2A and 5-HT2B receptor subtypes. Further optimization through replacement of the amide with a variety of five- and six-membered heterocycles led to the identification of 6-(1-ethyl-3-(quinolin-8-yl)-1H-pyrazol-5-yl)pyridazin-3-amine (69). Oral administration of 69 to rats reduced food intake in an ad libitum feeding model, which could be completely reversed by a selective 5-HT2C antagonist.- Published
- 2017
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