Discovery of Pre-Clinical Candidate <b>VU6008055</b>/<b>AF98943</b>: A Highly Selective, Orally Bioavailable, and Structurally Distinct Tricyclic M<sub>4</sub> Muscarinic Acetylcholine Receptor Positive Allosteric Modulator (PAM) with Robust In Vivo
Herein, we report the structure-activity relationship to develop novel tricyclic M<sub>4</sub> positive allosteric modulator scaffolds with improved pharmacological properties. This endeavor involved modifying a 5-amino-3,4-dimethylthieno[2,3-<i>c</i>]pyridazine-6-carboxamide core via a "tie-back" strategy to discover a novel tricyclic 3,4-dimethylpyrimido[4',5':4,5]thieno[2,3-<i>c</i>]pyridazine core. From this exercise, <b>VU6008055</b>/<b>AF98943</b> was identified as a preclinical candidate, which displays low nanomolar potency against both human and rat M<sub>4</sub>. Moreover, <b>VU6008055</b> is highly brain penetrant, has an overall superior pharmacological and DMPK profile to previously reported M<sub>4</sub> PAMs, and demonstrates efficacy in preclinical models of antipsychotic-like activity.
Authors
- Alison R. Gregro
- Thomas M. Bridges (ORCID: https://orcid.org/0000-0002-0491-4796)
- Alice L. Rodriguez (ORCID: https://orcid.org/0000-0002-5244-5103)
- Kayla J. Temple (ORCID: https://orcid.org/0000-0001-5290-574X)
- Michael Bubser (ORCID: https://orcid.org/0000-0002-0583-5248)
- John C. Gore (ORCID: https://orcid.org/0000-0002-9480-0900)
- Katherine J. Watson
- Nellie Byun
- Hyekyung P. Cho (ORCID: https://orcid.org/0000-0001-5393-2600)
- Darren W. Engers (ORCID: https://orcid.org/0000-0002-3633-3072)
- P. Jeffrey Conn (ORCID: https://orcid.org/0000-0003-2363-0323)
- Sean R. Bollinger
- Colleen M. Niswender (ORCID: https://orcid.org/0000-0001-6009-8212)
- W Hudson Robb (ORCID: https://orcid.org/0000-0002-8952-7719)
- Aidong Qi
- Carrie K. Jones (ORCID: https://orcid.org/0000-0002-1287-9839)
- Madeline F. Long (ORCID: https://orcid.org/0000-0002-8933-3439)
- Paul K. Spearing
- Robert W. Gould (ORCID: https://orcid.org/0000-0003-4861-1874)
- Craig W. Lindsley (ORCID: https://orcid.org/0000-0003-0168-1445)
- Vincent B. Luscombe (ORCID: https://orcid.org/0000-0002-2886-4017)
- Rory A. Capstick
- Olivier G. Boutaud (ORCID: https://orcid.org/0000-0002-8910-0598)
- Julie L. Engers (ORCID: https://orcid.org/0009-0004-3654-5464)
- Morten S. Thomsen (ORCID: https://orcid.org/0000-0002-5072-0351)
- Sichen Chang
- James C. Tarr
Institutions
- Society for Neuroscience (US)
- Allen Institute for Brain Science (US)
- Lundbeck (Denmark) (DK)
- Vanderbilt University (US)
- John F. Kennedy Center for the Performing Arts (US)
- Kennedy Center (DK)
- Center for Discovery (US)
- Vanderbilt Health (US)
- Vanderbilt University Medical Center (US)
Publication Details
- Journal
- ACS Chemical Neuroscience
- Published
- 2025-05-26
- DOI
- https://doi.org/10.1021/acschemneuro.5c00277
- Citations
- 2
- Primary Topic
- Receptor Mechanisms and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- William K. Warren Foundation
- National Institute of Mental Health