Structure-Activity Relationships for a Series of (Bis(4-fluorophenyl)methyl)sulfinyl Alkyl Alicyclic Amines at the Dopamine Transporter: Functionalizing the Terminal Nitrogen Affects Affinity, Selectivity, and Metabolic Stability

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Structure-Activity Relationships for a Series of (Bis(4-fluorophenyl)methyl)sulfinyl Alkyl Alicyclic Amines at the Dopamine Transporter : Functionalizing the Terminal Nitrogen Affects Affinity, Selectivity, and Metabolic Stability. / Slack, Rachel D.; Ku, Therese C.; Cao, Jianjing; Giancola, Jo Lynn B.; Bonifazi, Alessandro; Loland, Claus J.; Gadiano, Alexandra; Lam, Jenny; Rais, Rana; Slusher, Barbara S.; Coggiano, Mark; Tanda, Gianluigi; Newman, Amy Hauck.

In: Journal of Medicinal Chemistry, Vol. 63, No. 5, 2020, p. 2343-2357.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Slack, RD, Ku, TC, Cao, J, Giancola, JLB, Bonifazi, A, Loland, CJ, Gadiano, A, Lam, J, Rais, R, Slusher, BS, Coggiano, M, Tanda, G & Newman, AH 2020, 'Structure-Activity Relationships for a Series of (Bis(4-fluorophenyl)methyl)sulfinyl Alkyl Alicyclic Amines at the Dopamine Transporter: Functionalizing the Terminal Nitrogen Affects Affinity, Selectivity, and Metabolic Stability', Journal of Medicinal Chemistry, vol. 63, no. 5, pp. 2343-2357. https://doi.org/10.1021/acs.jmedchem.9b01188

APA

Slack, R. D., Ku, T. C., Cao, J., Giancola, J. L. B., Bonifazi, A., Loland, C. J., Gadiano, A., Lam, J., Rais, R., Slusher, B. S., Coggiano, M., Tanda, G., & Newman, A. H. (2020). Structure-Activity Relationships for a Series of (Bis(4-fluorophenyl)methyl)sulfinyl Alkyl Alicyclic Amines at the Dopamine Transporter: Functionalizing the Terminal Nitrogen Affects Affinity, Selectivity, and Metabolic Stability. Journal of Medicinal Chemistry, 63(5), 2343-2357. https://doi.org/10.1021/acs.jmedchem.9b01188

Vancouver

Slack RD, Ku TC, Cao J, Giancola JLB, Bonifazi A, Loland CJ et al. Structure-Activity Relationships for a Series of (Bis(4-fluorophenyl)methyl)sulfinyl Alkyl Alicyclic Amines at the Dopamine Transporter: Functionalizing the Terminal Nitrogen Affects Affinity, Selectivity, and Metabolic Stability. Journal of Medicinal Chemistry. 2020;63(5):2343-2357. https://doi.org/10.1021/acs.jmedchem.9b01188

Author

Slack, Rachel D. ; Ku, Therese C. ; Cao, Jianjing ; Giancola, Jo Lynn B. ; Bonifazi, Alessandro ; Loland, Claus J. ; Gadiano, Alexandra ; Lam, Jenny ; Rais, Rana ; Slusher, Barbara S. ; Coggiano, Mark ; Tanda, Gianluigi ; Newman, Amy Hauck. / Structure-Activity Relationships for a Series of (Bis(4-fluorophenyl)methyl)sulfinyl Alkyl Alicyclic Amines at the Dopamine Transporter : Functionalizing the Terminal Nitrogen Affects Affinity, Selectivity, and Metabolic Stability. In: Journal of Medicinal Chemistry. 2020 ; Vol. 63, No. 5. pp. 2343-2357.

Bibtex

@article{abeda83dfeff4949a2a067e127b852c5,
title = "Structure-Activity Relationships for a Series of (Bis(4-fluorophenyl)methyl)sulfinyl Alkyl Alicyclic Amines at the Dopamine Transporter: Functionalizing the Terminal Nitrogen Affects Affinity, Selectivity, and Metabolic Stability",
abstract = "Atypical dopamine transporter (DAT) inhibitors have shown therapeutic potential in preclinical models of psychostimulant abuse. In rats, 1-(4-(2-((bis(4-fluorophenyl)methyl)sulfinyl)ethyl)-piperazin-1-yl)-propan-2-ol (3b) was effective in reducing the reinforcing effects of both cocaine and methamphetamine but did not exhibit psychostimulant behaviors itself. While further development of 3b is ongoing, diastereomeric separation, as well as improvements in potency and pharmacokinetics were desirable for discovering pipeline drug candidates. Thus, a series of bis(4-fluorophenyl)methyl)sulfinyl)alkyl alicyclic amines, where the piperazine-2-propanol scaffold was modified, were designed, synthesized, and evaluated for binding affinities at DAT, as well as the serotonin transporter and σ1 receptors. Within the series, 14a showed improved DAT affinity (Ki = 23 nM) over 3b (Ki = 230 nM), moderate metabolic stability in human liver microsomes, and a hERG/DAT affinity ratio = 28. While 14a increased locomotor activity relative to vehicle, it was significantly lower than activity produced by cocaine. These results support further investigation of 14a as a potential treatment for psychostimulant use disorders.",
author = "Slack, {Rachel D.} and Ku, {Therese C.} and Jianjing Cao and Giancola, {Jo Lynn B.} and Alessandro Bonifazi and Loland, {Claus J.} and Alexandra Gadiano and Jenny Lam and Rana Rais and Slusher, {Barbara S.} and Mark Coggiano and Gianluigi Tanda and Newman, {Amy Hauck}",
year = "2020",
doi = "10.1021/acs.jmedchem.9b01188",
language = "English",
volume = "63",
pages = "2343--2357",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "5",

}

RIS

TY - JOUR

T1 - Structure-Activity Relationships for a Series of (Bis(4-fluorophenyl)methyl)sulfinyl Alkyl Alicyclic Amines at the Dopamine Transporter

T2 - Functionalizing the Terminal Nitrogen Affects Affinity, Selectivity, and Metabolic Stability

AU - Slack, Rachel D.

AU - Ku, Therese C.

AU - Cao, Jianjing

AU - Giancola, Jo Lynn B.

AU - Bonifazi, Alessandro

AU - Loland, Claus J.

AU - Gadiano, Alexandra

AU - Lam, Jenny

AU - Rais, Rana

AU - Slusher, Barbara S.

AU - Coggiano, Mark

AU - Tanda, Gianluigi

AU - Newman, Amy Hauck

PY - 2020

Y1 - 2020

N2 - Atypical dopamine transporter (DAT) inhibitors have shown therapeutic potential in preclinical models of psychostimulant abuse. In rats, 1-(4-(2-((bis(4-fluorophenyl)methyl)sulfinyl)ethyl)-piperazin-1-yl)-propan-2-ol (3b) was effective in reducing the reinforcing effects of both cocaine and methamphetamine but did not exhibit psychostimulant behaviors itself. While further development of 3b is ongoing, diastereomeric separation, as well as improvements in potency and pharmacokinetics were desirable for discovering pipeline drug candidates. Thus, a series of bis(4-fluorophenyl)methyl)sulfinyl)alkyl alicyclic amines, where the piperazine-2-propanol scaffold was modified, were designed, synthesized, and evaluated for binding affinities at DAT, as well as the serotonin transporter and σ1 receptors. Within the series, 14a showed improved DAT affinity (Ki = 23 nM) over 3b (Ki = 230 nM), moderate metabolic stability in human liver microsomes, and a hERG/DAT affinity ratio = 28. While 14a increased locomotor activity relative to vehicle, it was significantly lower than activity produced by cocaine. These results support further investigation of 14a as a potential treatment for psychostimulant use disorders.

AB - Atypical dopamine transporter (DAT) inhibitors have shown therapeutic potential in preclinical models of psychostimulant abuse. In rats, 1-(4-(2-((bis(4-fluorophenyl)methyl)sulfinyl)ethyl)-piperazin-1-yl)-propan-2-ol (3b) was effective in reducing the reinforcing effects of both cocaine and methamphetamine but did not exhibit psychostimulant behaviors itself. While further development of 3b is ongoing, diastereomeric separation, as well as improvements in potency and pharmacokinetics were desirable for discovering pipeline drug candidates. Thus, a series of bis(4-fluorophenyl)methyl)sulfinyl)alkyl alicyclic amines, where the piperazine-2-propanol scaffold was modified, were designed, synthesized, and evaluated for binding affinities at DAT, as well as the serotonin transporter and σ1 receptors. Within the series, 14a showed improved DAT affinity (Ki = 23 nM) over 3b (Ki = 230 nM), moderate metabolic stability in human liver microsomes, and a hERG/DAT affinity ratio = 28. While 14a increased locomotor activity relative to vehicle, it was significantly lower than activity produced by cocaine. These results support further investigation of 14a as a potential treatment for psychostimulant use disorders.

U2 - 10.1021/acs.jmedchem.9b01188

DO - 10.1021/acs.jmedchem.9b01188

M3 - Journal article

C2 - 31661268

AN - SCOPUS:85075585677

VL - 63

SP - 2343

EP - 2357

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 5

ER -

ID: 236990803