Austen Brooks Casey

All Publications

• "Selective" serotonin 5-HT2A receptor antagonists. Biochemical pharmacology Casey, A. B., Cui, M., Booth, R. G., Canal, C. E. 2022: 115028

  Abstract

  Blockade of the serotonin 5-HT2A G protein-coupled receptor (5-HT2AR) 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-HT2AR by serotonergic psychedelics may be useful in treating neuropsychiatric indications, including major depressive and substance use disorders. Serotonergic psychedelics and other 5-HT2AR agonists, however, often bind other receptors, and standard 5-HT2AR antagonists lack sufficient selectivity to make well-founded mechanistic conclusions about the 5-HT2AR-dependent effects of these compounds and the general neurobiological function of 5-HT2ARs. This review discusses the limitations and strengths of currently available "selective" 5-HT2AR antagonists, the molecular determinants of antagonist selectivity at 5-HT2ARs, and the utility of molecular pharmacological and computational methods in guiding the discovery of novel unambiguously selective 5-HT2AR antagonists.

  View details for DOI 10.1016/j.bcp.2022.115028

  View details for PubMedID 35381208

• A new class of serotonin 5-HT2A/5-HT2C receptor inverse agonists: Synthesis, molecular modeling, in vitro and in vivo pharmacology of novel 2-aminotetralins British Journal of Pharacology Casey, A. B., Mukherjee, M., McGlynn, R. P., Cui, M., Kohut, S. J., Booth, R. G. 2021

  View details for DOI 10.1111/bph.15756

• (S)-5-(2 '-Fluorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine, a Serotonin Receptor Modulator, Possesses Anticonvulsant, Prosocial, and Anxiolytic-like Properties in an Fmr1 Knockout Mouse Model of Fragile X Syndrome and Autism Spectrum Disorder ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE Armstrong, J. L., Casey, A. B., Saraf, T. S., Mukherjee, M., Booth, R. G., Canal, C. E. 2020; 3 (3): 509-523

  Abstract

  Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by intellectual disabilities and a plethora of neuropsychiatric symptoms. FXS is the leading monogenic cause of autism spectrum disorder (ASD), which is defined clinically by repetitive and/or restrictive patterns of behavior and social communication deficits. Epilepsy and anxiety are also common in FXS and ASD. Serotonergic neurons directly innervate and modulate the activity of neurobiological circuits altered in both disorders, providing a rationale for investigating serotonin receptors (5-HTRs) as targets for FXS and ASD drug discovery. Previously we unveiled an orally active aminotetralin, (S)-5-(2'-fluorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (FPT), that exhibits partial agonist activity at 5-HT1ARs, 5-HT2CRs, and 5-HT7Rs and that reduces repetitive behaviors and increases social approach behavior in wild-type mice. Here we report that in an Fmr1 knockout mouse model of FXS and ASD, FPT is prophylactic for audiogenic seizures. No FPT-treated mice displayed audiogenic seizures, compared to 73% of vehicle-treated mice. FPT also exhibits anxiolytic-like effects in several assays and increases social interactions in both Fmr1 knockout and wild-type mice. Furthermore, FPT increases c-Fos expression in the basolateral amygdala, which is a preclinical effect produced by anxiolytic medications. Receptor pharmacology assays show that FPT binds competitively and possesses rapid association and dissociation kinetics at 5-HT1ARs and 5-HT7Rs, yet has slow association and rapid dissociation kinetics at 5-HT2CRs. Finally, we reassessed and report FPT's affinity and function at 5-HT1ARs, 5-HT2CRs, and 5-HT7Rs. Collectively, these observations provide mounting support for further development of FPT as a pharmacotherapy for common neuropsychiatric symptoms in FXS and ASD.

  View details for DOI 10.1021/acsptsci.9b00101

  View details for Web of Science ID 000604267300012

  View details for PubMedID 32566916

  View details for PubMedCentralID PMC7296548

• Synthesis of novel 5-substituted-2-aminotetralin analogs: 5-HT1A and 5-HT7 G protein-coupled receptor affinity, 3D-QSAR and molecular modeling BIOORGANIC & MEDICINAL CHEMISTRY Perry, C. K., Casey, A. B., Felsing, D. E., Vemula, R., Zaka, M., Herrington, N. B., Cui, M., Kellogg, G. E., Canal, C. E., Booth, R. G. 2020; 28 (3): 115262

  Abstract

  The serotonin 5-HT7 G protein-coupled receptor (GPCR) is a proposed pharmacotherapeutic target for a variety of central and peripheral indications, albeit, there are no approved drugs selective for binding 5-HT7. We previously reported that a lead analog based on the 5-substituted-N,N-disubstituted-1,2,3,4-tetrahydronaphthalen-2-amine (5-substituted-2-aminotetralin, 5-SAT) scaffold binds with high affinity at the 5-HT7 GPCR, and can treat symptoms of autism in mouse models; subsequently, the lead was found to have high affinity at the 5-HT1A GPCR. Herein, we report the synthesis of novel 5-SAT analogs to develop a 3-dimensional quantitative structure-affinity relationship (3D-QSAR) at the human 5-HT7 receptor for comparison with similar studies at the highly homologous 5-HT1A receptor. We report 35 new 5-SAT ligands, some with very high affinity (Ki ≤ 1 nM) and stereoselectivity at 5-HT7 + or 5-HT1A receptors, several with modest selectivity (up to 12-fold) for binding at 5-HT7, and, several ligands with high selectivity (up to 40-fold) at the 5-HT1A receptor. 3D-QSAR results indicate that steric extensions at the C(5)-position improve selectivity for the 5-HT7 over 5-HT1A receptor, while steric and hydrophobic extensions at the chiral C(2)-amino position impart 5-HT1A selectivity. In silico receptor homology modeling studies, supplemented with molecular dynamics simulations and binding free energy calculations, were used to rationalize experimentally-determined receptor selectivity and stereoselective affinity results. The data from these studies indicate that the 5-SAT chemotype, previously shown to be safe and efficacious in rodent paradigms of neurodevelopmental and neuropsychiatric disorders, is amenable to structural modification to optimize affinity at serotonin 5-HT7 vs. 5-HT1A GPCRs, as may be required for successful clinical translation.

  View details for DOI 10.1016/j.bmc.2019.115262

  View details for Web of Science ID 000507466200009

  View details for PubMedID 31882369

• Classics in Chemical Neuroscience: Aripiprazole ACS CHEMICAL NEUROSCIENCE Casey, A. B., Canal, C. E. 2017; 8 (6): 1135-1146

  Abstract

  Aripiprazole was the first antipsychotic developed to possess agonist properties at dopamine D2 autoreceptors, a groundbreaking strategy that presented a new vista for schizophrenia drug discovery. The dopamine D2 receptor is the crucial target of all extant antipsychotics, and all developed prior to aripiprazole were D2 receptor antagonists. Extensive blockade of these receptors, however, typically produces extrapyramidal (movement) side effects, which plagued first-generation antipsychotics, such as haloperidol. Second-generation antipsychotics, such as clozapine, with unique polypharmacology and D2 receptor binding kinetics, have significantly lower risk of movement side effects but can cause myriad additional ones, such as severe weight gain and metabolic dysfunction. Aripiprazole's polypharmacology, characterized by its unique agonist activity at dopamine D2 and D3 and serotonin 5-HT1A receptors, as well as antagonist activity at serotonin 5-HT2A receptors, translates to successful reduction of positive, negative, and cognitive symptoms of schizophrenia, while also mitigating risk of weight gain and movement side effects. New observations, however, link aripiprazole to compulsive behaviors in a small group of patients, an unusual side effect for antipsychotics. In this review, we discuss the chemical synthesis, pharmacology, pharmacogenomics, drug metabolism, and adverse events of aripiprazole, and we present a current understanding of aripiprazole's neurotherapeutic mechanisms, as well as the history and importance of aripiprazole to neuroscience.

  View details for DOI 10.1021/acschemneuro.7b00087

  View details for Web of Science ID 000404098100004

  View details for PubMedID 28368577

  View details for PubMedCentralID PMC5495458