Further exploration of 1-{2-[Bis-(4-fluorophenyl)methoxy]ethyl}piperazine (GBR 12909): Role of N-aromatic, N-heteroaromatic, and 3-oxygenated N-phenylpropyl substituents on affinity for the dopamine and serotonin transporter

David Lewis; Ying Zhang; Thomas Prisinzano; Christina M. Dersch; Richard B. Rothman; Arthur E. Jacobson; Kenner C. Rice

doi:10.1016/S0960-894X(03)00108-2

Further exploration of 1-{2-[Bis-(4-fluorophenyl)methoxy]ethyl}piperazine (GBR 12909): Role of N-aromatic, N-heteroaromatic, and 3-oxygenated N-phenylpropyl substituents on affinity for the dopamine and serotonin transporter

David Lewis, Ying Zhang, Thomas Prisinzano, Christina M. Dersch, Richard B. Rothman, Arthur E. Jacobson, Kenner C. Rice

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

11 Scopus citations

Abstract

A series of N-aromatic, N-heteroaromatic, and oxygenated N-phenylpropyl derivatives of 1-(2-benzhydryloxyethyl)-piperazine and 1-{2-[bis-(4-fluorophenyl)methoxy]ethyl}piperazine, analogues of GBR 12909 (1a) and 12935 (1b), was synthesized and examined for their dopamine (DAT) and serotonin (SERT) transporter binding properties. One of these compounds, racemic 3-[4-(2-benzhydryloxyethyl)piperazin-1-yl]-1-(3-fluorophenyl)-propan-1-ol (33), had DAT affinity as good as, or better than, GBR 12909 and 12935, and was more selective for DAT over SERT than the GBR compounds. Both trans- (43) and cis- (47) (±)-2-(4-{2-[bis-(4-fluorophenyl)-methoxy]ethyl}piperazin-1- ylmethyl)-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-ol had relatively good SERT selectivity and, as well, showed high affinity for SERT.

Original language	English
Pages (from-to)	1385-1389
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	13
Issue number	7
DOIs	https://doi.org/10.1016/S0960-894X(03)00108-2
State	Published - Apr 7 2003

Bibliographical note

Funding Information:
The authors (LMC, NIDDK) thank the National Institute on Drug Abuse, NIH, for partial financial support of our research program. We also thank Noel Whittaker (NIDDK, NIH) for mass spectral data.

Funding

The authors (LMC, NIDDK) thank the National Institute on Drug Abuse, NIH, for partial financial support of our research program. We also thank Noel Whittaker (NIDDK, NIH) for mass spectral data.

Funders	Funder number
National Institutes of Health (NIH)
National Institute on Drug Abuse
National Institute of Diabetes and Digestive and Kidney Diseases	Z01DK059501

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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Lewis, D., Zhang, Y., Prisinzano, T., Dersch, C. M., Rothman, R. B., Jacobson, A. E., & Rice, K. C. (2003). Further exploration of 1-{2-[Bis-(4-fluorophenyl)methoxy]ethyl}piperazine (GBR 12909): Role of N-aromatic, N-heteroaromatic, and 3-oxygenated N-phenylpropyl substituents on affinity for the dopamine and serotonin transporter. Bioorganic and Medicinal Chemistry Letters, 13(7), 1385-1389. https://doi.org/10.1016/S0960-894X(03)00108-2

Lewis, David ; Zhang, Ying ; Prisinzano, Thomas et al. / Further exploration of 1-{2-[Bis-(4-fluorophenyl)methoxy]ethyl}piperazine (GBR 12909) : Role of N-aromatic, N-heteroaromatic, and 3-oxygenated N-phenylpropyl substituents on affinity for the dopamine and serotonin transporter. In: Bioorganic and Medicinal Chemistry Letters. 2003 ; Vol. 13, No. 7. pp. 1385-1389.

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title = "Further exploration of 1-{2-[Bis-(4-fluorophenyl)methoxy]ethyl}piperazine (GBR 12909): Role of N-aromatic, N-heteroaromatic, and 3-oxygenated N-phenylpropyl substituents on affinity for the dopamine and serotonin transporter",

abstract = "A series of N-aromatic, N-heteroaromatic, and oxygenated N-phenylpropyl derivatives of 1-(2-benzhydryloxyethyl)-piperazine and 1-{2-[bis-(4-fluorophenyl)methoxy]ethyl}piperazine, analogues of GBR 12909 (1a) and 12935 (1b), was synthesized and examined for their dopamine (DAT) and serotonin (SERT) transporter binding properties. One of these compounds, racemic 3-[4-(2-benzhydryloxyethyl)piperazin-1-yl]-1-(3-fluorophenyl)-propan-1-ol (33), had DAT affinity as good as, or better than, GBR 12909 and 12935, and was more selective for DAT over SERT than the GBR compounds. Both trans- (43) and cis- (47) (±)-2-(4-{2-[bis-(4-fluorophenyl)-methoxy]ethyl}piperazin-1- ylmethyl)-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-ol had relatively good SERT selectivity and, as well, showed high affinity for SERT.",

author = "David Lewis and Ying Zhang and Thomas Prisinzano and Dersch, {Christina M.} and Rothman, {Richard B.} and Jacobson, {Arthur E.} and Rice, {Kenner C.}",

note = "Funding Information: The authors (LMC, NIDDK) thank the National Institute on Drug Abuse, NIH, for partial financial support of our research program. We also thank Noel Whittaker (NIDDK, NIH) for mass spectral data. ",

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Lewis, D, Zhang, Y, Prisinzano, T, Dersch, CM, Rothman, RB, Jacobson, AE & Rice, KC 2003, 'Further exploration of 1-{2-[Bis-(4-fluorophenyl)methoxy]ethyl}piperazine (GBR 12909): Role of N-aromatic, N-heteroaromatic, and 3-oxygenated N-phenylpropyl substituents on affinity for the dopamine and serotonin transporter', Bioorganic and Medicinal Chemistry Letters, vol. 13, no. 7, pp. 1385-1389. https://doi.org/10.1016/S0960-894X(03)00108-2

Further exploration of 1-{2-[Bis-(4-fluorophenyl)methoxy]ethyl}piperazine (GBR 12909): Role of N-aromatic, N-heteroaromatic, and 3-oxygenated N-phenylpropyl substituents on affinity for the dopamine and serotonin transporter. / Lewis, David; Zhang, Ying; Prisinzano, Thomas et al.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 13, No. 7, 07.04.2003, p. 1385-1389.

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

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T1 - Further exploration of 1-{2-[Bis-(4-fluorophenyl)methoxy]ethyl}piperazine (GBR 12909)

T2 - Role of N-aromatic, N-heteroaromatic, and 3-oxygenated N-phenylpropyl substituents on affinity for the dopamine and serotonin transporter

AU - Lewis, David

AU - Zhang, Ying

AU - Prisinzano, Thomas

AU - Dersch, Christina M.

AU - Rothman, Richard B.

AU - Jacobson, Arthur E.

AU - Rice, Kenner C.

N1 - Funding Information: The authors (LMC, NIDDK) thank the National Institute on Drug Abuse, NIH, for partial financial support of our research program. We also thank Noel Whittaker (NIDDK, NIH) for mass spectral data.

PY - 2003/4/7

Y1 - 2003/4/7

N2 - A series of N-aromatic, N-heteroaromatic, and oxygenated N-phenylpropyl derivatives of 1-(2-benzhydryloxyethyl)-piperazine and 1-{2-[bis-(4-fluorophenyl)methoxy]ethyl}piperazine, analogues of GBR 12909 (1a) and 12935 (1b), was synthesized and examined for their dopamine (DAT) and serotonin (SERT) transporter binding properties. One of these compounds, racemic 3-[4-(2-benzhydryloxyethyl)piperazin-1-yl]-1-(3-fluorophenyl)-propan-1-ol (33), had DAT affinity as good as, or better than, GBR 12909 and 12935, and was more selective for DAT over SERT than the GBR compounds. Both trans- (43) and cis- (47) (±)-2-(4-{2-[bis-(4-fluorophenyl)-methoxy]ethyl}piperazin-1- ylmethyl)-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-ol had relatively good SERT selectivity and, as well, showed high affinity for SERT.

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Lewis D, Zhang Y, Prisinzano T, Dersch CM, Rothman RB, Jacobson AE et al. Further exploration of 1-{2-[Bis-(4-fluorophenyl)methoxy]ethyl}piperazine (GBR 12909): Role of N-aromatic, N-heteroaromatic, and 3-oxygenated N-phenylpropyl substituents on affinity for the dopamine and serotonin transporter. Bioorganic and Medicinal Chemistry Letters. 2003 Apr 7;13(7):1385-1389. doi: 10.1016/S0960-894X(03)00108-2

Further exploration of 1-{2-[Bis-(4-fluorophenyl)methoxy]ethyl}piperazine (GBR 12909): Role of N-aromatic, N-heteroaromatic, and 3-oxygenated N-phenylpropyl substituents on affinity for the dopamine and serotonin transporter

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

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