Bryan L. Roth

This paper introduces engineered mouse models to study the effects of psychedelic drugs by examining HTR2A receptor expression and function.

The paper uses cryo-EM to analyze endogenous mGluR2-containing receptor assemblies in mouse brain, revealing distinct structural states and complexes not previously observed in recombinant systems.

The paper investigates whether mGluR2 and 5-HT2A receptors physically interact in vitro or in vivo and finds no evidence for direct interaction or oligomerization.

This study systematically evaluates the effectiveness of random small perturbations in ligand optimization, finding 11.2% of analogs improved potency by ≥10-fold but often had worse pharmacokinetics.

The paper tests if molecules from ultra-large libraries are more selective than those from bio-like libraries, finding similar off-target activity despite differences in chemical novelty.

This study investigates the polypharmacological profiles of xanomeline and its metabolite N-desmethylxanomeline, revealing their agonist and antagonist actions at multiple biogenic amine G protein-coupled receptors.

The paper investigates whether other FDA-approved alpha2-adrenergic agonists share xylazine's kappa opioid agonist activity and finds they do not, but have distinct GPCR activity patterns.

The paper examines how sodium ions differentially modulate agonist-induced conformational changes and signaling at μ and κ opioid receptors, revealing opposing effects between the two receptor types.

This paper presents computational methods for designing GPCR-binding miniproteins and validates them through high-throughput screening, producing agonists and antagonists for multiple GPCRs.

This paper introduces a scalable proximity proteomics pipeline that improves reproducibility and throughput in biotinylation-based spatial proteomics.

The paper identifies the serotonin 1F receptor as a negative regulator of human beta cell survival during transplant and demonstrates a small molecule antagonist that improves glycemia in islet transplants.

This study shows that activity-dependent alternative splicing of Latrophilin-3 controls synapse formation through dual pathways involving GS/cAMP signaling and phase-separated protein scaffolds.

This study shows xylazine acts as a kappa opioid receptor agonist and that naloxone induces withdrawal from xylazine and fentanyl/xylazine combinations, with greater sensitivity in females.

This study uses a generative deep learning framework to design new KOR antagonists, which are prioritized for synthesis and validated through experimental assays.

This study shows psilocin excites 5-HT2A Layer 5 Pyramidal Neurons in the mouse PFC via a Gq-mediated mechanism, increasing firing without affecting synaptic transmission.

The paper examines how non-synonymous SNPs in the 5-HT2A receptor gene affect the potency and efficacy of four psychedelic drugs in vitro.

The paper evaluates druggable genes in mice and finds that many understudied ones have significant phenotypes similar to human diseases, suggesting therapeutic potential.

The paper characterizes two MOR PAMs that enhance opioid antinociception without increasing adverse effects in mouse models.

The paper reports the structures of D1R-Gs complex bound to dopamine and LY3154207, revealing mechanisms of dopamine recognition and allosteric modulation for drug discovery.

This study investigates how LSD affects behavior in mice lacking beta-arrestin 1 or 2, revealing distinct roles for these proteins in mediating LSD's effects.

This paper introduces deschloroclozapine (DCZ), a potent and selective DREADD agonist that rapidly modulates neuronal activity and behavior in mice and monkeys.

The paper introduces GA-PAIR, a chemogenetic platform that enables precise spatio-temporal control of β-arrestin signaling in GPCRs using ABA-induced protein interactions.

This paper introduces a 3D molecular representation (E3FP) that improves drug-to-target prediction compared to 2D fingerprints, with experimental validation of novel binding predictions.

This study shows that deleting RSK2 in mice increases psychostimulant responses and 5-HT2A receptor signaling, linking RSK2 dysfunction to schizophrenia-like behaviors in Coffin-Lowry Syndrome.