2. Academic Validation
  3. Pharmacology and Therapeutic Potential of Benzothiazole Analogues for Cocaine Use Disorder

Pharmacology and Therapeutic Potential of Benzothiazole Analogues for Cocaine Use Disorder

  • J Med Chem. 2023 Sep 14;66(17):12141-12162. doi: 10.1021/acs.jmedchem.3c00734.
Comfort A Boateng 1,  Ashley N Nilson 2,  Rebekah Placide 1,  Mimi L Pham 1,  Franziska M Jakobs 1,  Noelia Boldizsar 2,  Scot McIntosh 1,  Leia S Stallings 1,  Ivana V Korankyi 1,  Shreya Kelshikar 3,  Nisha Shah 3,  Diandra Panasis 3,  Abigail Muccilli 3,  Maria Ladik 3,  Brianna Maslonka 3,  Connor McBride 3,  Moises Ximello Sanchez 3,  Ebrar Akca 3,  Mohammad Alkhatib 3,  Julianna Saez 3,  Catherine Nguyen 3,  Emily Kurtyan 3,  Jacquelyn DePierro 3,  Raymond Crowthers 3,  Dylan Brunt 3,  Alessandro Bonifazi 4,  Amy Hauck Newman 4,  Rana Rais 5,  Barbara S Slusher 5,  R Benjamin Free 2,  David R Sibley 2,  Kent D Stewart 1,  Chun Wu 3,  Scott E Hemby 1,  Thomas M Keck 3
Affiliations

Affiliations

  • 1 Department of Basic Pharmaceutical Sciences, Fred Wilson School of Pharmacy, High Point University, One University Parkway, High Point, North Carolina 27268, United States.
  • 2 Molecular Neuropharmacology Section, National Institute of Neurological Disorders and Stroke-Intramural Research Program, National Institutes of Health, Bethesda, Maryland 20892, United States.
  • 3 Department of Chemistry & Biochemistry, Department of Biological & Biomedical Sciences, College of Science and Mathematics, Rowan University, 201 Mullica Hill Road, Glassboro, New Jersey 08028, United States.
  • 4 Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, Maryland 21224, United States.
  • 5 Department of Neurology, Johns Hopkins Drug Discovery, The Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, Maryland 21205, United States.
PMID: 37646374 DOI: 10.1021/acs.jmedchem.3c00734
Abstract

Pharmacological targeting of the dopamine D4 receptor (D4R)─expressed in brain regions that control cognition, attention, and decision-making─could be useful for several neuropsychiatric disorders including substance use disorders (SUDs). This study focused on the synthesis and evaluation of a novel series of benzothiazole analogues designed to target D4R. We identified several compounds with high D4R binding affinity (Ki ≤ 6.9 nM) and >91-fold selectivity over other D2-like receptors (D2R, D3R) with diverse partial agonist and antagonist profiles. Novel analogue 16f is a potent low-efficacy D4R partial agonist, metabolically stable in rat and human liver microsomes, and has excellent brain penetration in rats (AUCbrain/plasma > 3). 16f (5-30 mg/kg, i.p.) dose-dependently decreased iv cocaine self-administration in rats, consistent with previous results produced by D4R-selective antagonists. Off-target antagonism of 5-HT2A or 5-HT2B may also contribute to these effects. Results with 16f support further efforts to target D4R in SUD treatment.

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