The serotonin (5-hydroxytryptamine, 5-HT) 5-HT₁ G-protein coupled receptor subtypes (5-HT_{1A/1B/1D/1E/1F}) share a high sequence homology, confounding development of subtype-specific ligands. This project uses a 5-HT₁ structure-based ligand design approach to develop subtype-selective ligands using a 5-substituted-2-aminotetralin (5-SAT) chemotype, leveraging results from pharmacological, molecular modeling, and mutagenesis studies to delineate molecular determinants for 5-SAT binding and function at 5-HT₁ subtypes.

The serotonin (5-HT) 5-HT₆ receptor is a G protein-coupled receptor almost exclusively expressed in the central nervous system that is believed to play a role in neuroplasticity and cognitive function. Both activation and inhibition of the 5-HT₆R has been linked to pro-cognitive effects, indicating it is a therapeutically relevant target for disorders that involve cognitive deficit symptoms, including Alzheimer’s disease and schizophrenia. Several potent 5-HT₆R antagonists have entered clinical trials for Alzheimer’s disease and schizophrenia, but all have failed to gain FDA approval. Our lab has developed novel compounds based on the 2-aminotetralin scaffold to target this receptor with a particular focus on the 7-substituted-2-aminotetralin chemotype. Current efforts aim to further optimize our compounds through a structure-activity relationship study and pharmacologically evaluate lead compounds in vitro and in vivo.

Many important physiological processes are mediated by alpha2A- and alpha2C-adrenergic receptors (α2Rs), a subtype of class A G protein-coupled receptors. However, α2R signaling is poorly understood, and there are few approved medications targeting these receptors. Drug discovery aimed at α2Rs is complicated by the high degree of binding pocket homology between α2AR and α2CR, which confounds ligand-mediated selective activation or inactivation of signaling associated with a particular subtype. Meanwhile, α2R signaling is complex and it is reported that activating α2AR is beneficial in many clinical contexts, while activating α2CR signaling may be detrimental to these positive effects. Current efforts in the lab aim to use the novel 5-substituted-2-aminotetralin chemotype to selectively target both the α2AR and the α2CR. The project also aims to understand ligand stabilization of functionally distinct GPCR conformations regarding α2AR and α2CRs.

Blockade of the serotonin 5-HT_2A G protein-coupled receptor (5-HT_2AR) is a fundamental pharmacological characteristic of numerous antipsychotic medications, which are FDA-approved to treat schizophrenia, bipolar disorder, and as adjunctive therapies in major depressive disorder. Meanwhile, activation of the 5-HT_2AR by serotonergic psychedelics may be useful in treating neuropsychiatric indications, including major depressive and substance use disorders. Serotonergic psychedelics and other 5-HT_2AR agonists, however, often bind other receptors, and standard 5-HT_2AR antagonists lack sufficient selectivity to make well-founded mechanistic conclusions about the 5-HT_2AR -dependent effects of these compounds and the general neurobiological function of 5-HT_2ARs. Current efforts in the lab aim to yield selective 5-HT_2A/5-HT_2C receptor inverse agonists for antipsychotic drug development