Pharmacology and Therapeutic Potential of Benzothiazole Analogues for Cocaine Use Disorder

Comfort A. Boateng; Ashley N. Nilson; Rebekah Placide; Mimi L. Pham; Franziska M. Jakobs; Noelia Boldizsar; Scot McIntosh; Leia S. Stallings; Ivana V. Korankyi; Shreya Kelshikar; Nisha Shah; Diandra Panasis; Abigail Muccilli; Maria Ladik; Brianna Maslonka; Connor McBride; Moises Ximello Sanchez; Ebrar Akca; Mohammad Alkhatib; Julianna Saez; Catherine Nguyen; Emily Kurtyan; Jacquelyn DePierro; Raymond Crowthers; Dylan Brunt; Alessandro Bonifazi; Amy Hauck Newman; Rana Rais; Barbara S. Slusher; R. Benjamin Free; David R. Sibley; Kent D. Stewart; Chun Wu; Scott E. Hemby; Thomas M. Keck

doi:10.1021/acs.jmedchem.3c00734

Pharmacology and Therapeutic Potential of Benzothiazole Analogues for Cocaine Use Disorder

Comfort A. Boateng, Ashley N. Nilson, Rebekah Placide, Mimi L. Pham, Franziska M. Jakobs, Noelia Boldizsar, Scot McIntosh, Leia S. Stallings, Ivana V. Korankyi, Shreya Kelshikar, Nisha Shah, Diandra Panasis, Abigail Muccilli, Maria Ladik, Brianna Maslonka, Connor McBride, Moises Ximello Sanchez, Ebrar Akca, Mohammad Alkhatib, Julianna SaezCatherine Nguyen, Emily Kurtyan, Jacquelyn DePierro, Raymond Crowthers, Dylan Brunt, Alessandro Bonifazi, Amy Hauck Newman, Rana Rais, Barbara S. Slusher, R. Benjamin Free, David R. Sibley, Kent D. Stewart, Chun Wu, Scott E. Hemby, Thomas M. Keck

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

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 (K_i ≤ 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 (AUC_brain/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-HT_2A or 5-HT_2B may also contribute to these effects. Results with 16f support further efforts to target D₄R in SUD treatment.

Original language	English (US)
Pages (from-to)	12141-12162
Number of pages	22
Journal	Journal of medicinal chemistry
Volume	66
Issue number	17
DOIs	https://doi.org/10.1021/acs.jmedchem.3c00734
State	Published - Sep 14 2023
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1021/acs.jmedchem.3c00734

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Boateng, C. A., Nilson, A. N., Placide, R., Pham, M. L., Jakobs, F. M., Boldizsar, N., McIntosh, S., Stallings, L. S., Korankyi, I. V., Kelshikar, S., Shah, N., Panasis, D., Muccilli, A., Ladik, M., Maslonka, B., McBride, C., Sanchez, M. X., Akca, E., Alkhatib, M., ... Keck, T. M. (2023). Pharmacology and Therapeutic Potential of Benzothiazole Analogues for Cocaine Use Disorder. Journal of medicinal chemistry, 66(17), 12141-12162. https://doi.org/10.1021/acs.jmedchem.3c00734

Boateng, CA, Nilson, AN, Placide, R, Pham, ML, Jakobs, FM, Boldizsar, N, McIntosh, S, Stallings, LS, Korankyi, IV, Kelshikar, S, Shah, N, Panasis, D, Muccilli, A, Ladik, M, Maslonka, B, McBride, C, Sanchez, MX, Akca, E, Alkhatib, M, Saez, J, Nguyen, C, Kurtyan, E, DePierro, J, Crowthers, R, Brunt, D, Bonifazi, A, Newman, AH, Rais, R, Slusher, BS, Free, RB, Sibley, DR, Stewart, KD, Wu, C, Hemby, SE & Keck, TM 2023, 'Pharmacology and Therapeutic Potential of Benzothiazole Analogues for Cocaine Use Disorder', Journal of medicinal chemistry, vol. 66, no. 17, pp. 12141-12162. https://doi.org/10.1021/acs.jmedchem.3c00734

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title = "Pharmacology and Therapeutic Potential of Benzothiazole Analogues for Cocaine Use Disorder",

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.",

author = "Boateng, {Comfort A.} and Nilson, {Ashley N.} and Rebekah Placide and Pham, {Mimi L.} and Jakobs, {Franziska M.} and Noelia Boldizsar and Scot McIntosh and Stallings, {Leia S.} and Korankyi, {Ivana V.} and Shreya Kelshikar and Nisha Shah and Diandra Panasis and Abigail Muccilli and Maria Ladik and Brianna Maslonka and Connor McBride and Sanchez, {Moises Ximello} and Ebrar Akca and Mohammad Alkhatib and Julianna Saez and Catherine Nguyen and Emily Kurtyan and Jacquelyn DePierro and Raymond Crowthers and Dylan Brunt and Alessandro Bonifazi and Newman, {Amy Hauck} and Rana Rais and Slusher, {Barbara S.} and Free, {R. Benjamin} and Sibley, {David R.} and Stewart, {Kent D.} and Chun Wu and Hemby, {Scott E.} and Keck, {Thomas M.}",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors. Published by American Chemical Society.",

year = "2023",

month = sep,

day = "14",

doi = "10.1021/acs.jmedchem.3c00734",

language = "English (US)",

volume = "66",

pages = "12141--12162",

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T1 - Pharmacology and Therapeutic Potential of Benzothiazole Analogues for Cocaine Use Disorder

AU - Boateng, Comfort A.

AU - Nilson, Ashley N.

AU - Placide, Rebekah

AU - Pham, Mimi L.

AU - Jakobs, Franziska M.

AU - Boldizsar, Noelia

AU - McIntosh, Scot

AU - Stallings, Leia S.

AU - Korankyi, Ivana V.

AU - Kelshikar, Shreya

AU - Shah, Nisha

AU - Panasis, Diandra

AU - Muccilli, Abigail

AU - Ladik, Maria

AU - Maslonka, Brianna

AU - McBride, Connor

AU - Sanchez, Moises Ximello

AU - Akca, Ebrar

AU - Alkhatib, Mohammad

AU - Saez, Julianna

AU - Nguyen, Catherine

AU - Kurtyan, Emily

AU - DePierro, Jacquelyn

AU - Crowthers, Raymond

AU - Brunt, Dylan

AU - Bonifazi, Alessandro

AU - Newman, Amy Hauck

AU - Rais, Rana

AU - Slusher, Barbara S.

AU - Free, R. Benjamin

AU - Sibley, David R.

AU - Stewart, Kent D.

AU - Wu, Chun

AU - Hemby, Scott E.

AU - Keck, Thomas M.

PY - 2023/9/14

Y1 - 2023/9/14

N2 - 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.

AB - 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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DO - 10.1021/acs.jmedchem.3c00734

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C2 - 37646374

AN - SCOPUS:85171309542

SN - 0022-2623

VL - 66

SP - 12141

EP - 12162

JO - Journal of medicinal chemistry

JF - Journal of medicinal chemistry

IS - 17

ER -

Pharmacology and Therapeutic Potential of Benzothiazole Analogues for Cocaine Use Disorder

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