Design, synthesis, and monoamine transporter binding site affinities of methoxy derivatives of indatraline

X H Gu; H Yu; A E Jacobson; R B Rothman; C M Dersch; C George; J L Flippen-Anderson; K C Rice

doi:10.1021/jm000329v

Design, synthesis, and monoamine transporter binding site affinities of methoxy derivatives of indatraline

J Med Chem. 2000 Dec 14;43(25):4868-76. doi: 10.1021/jm000329v.

Authors

X H Gu¹, H Yu, A E Jacobson, R B Rothman, C M Dersch, C George, J L Flippen-Anderson, K C Rice

Affiliation

¹ Laboratory of Medicinal Chemistry, Building 8, Room B1-23, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0815, USA.

PMID: 11123996
DOI: 10.1021/jm000329v

Abstract

A series of methoxy-containing derivatives of indatraline 13a-f and 17 were synthesized, and their binding affinities for the dopamine, serotonin, and norepinephrine transporter binding sites were determined. Introduction of a methoxy group to indatraline affected its affinity and selectivity greatly. Except for the 4-methoxy derivative 13a,which had the same high affinity at the dopamine transporter binding site as indatraline, the other methoxy-containing analogues (13b-f and 17) exhibited lower affinity than indatraline for the three transporter binding sites. However, some of the analogues were more selective than indatraline, and the 6-methoxy derivative 13c displayed the highest affinity for both the serotonin and norepinephrine transporters. This compound retained reasonable affinity for the dopamine transporter and is a promising template for the development of a long-acting inhibitor of monoamine transporters. Such inhibitors have potential as medications for treatment, as a substitution medication, or for prevention of the abuse of methamphetamine-like stimulants.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Animals
Binding, Competitive
Carrier Proteins / metabolism*
Crystallography, X-Ray
Dopamine / metabolism*
Dopamine Plasma Membrane Transport Proteins
Drug Design
Indans / chemical synthesis*
Indans / chemistry
Indans / metabolism
Membrane Glycoproteins / metabolism*
Membrane Transport Proteins*
Methylamines / chemical synthesis*
Methylamines / chemistry
Methylamines / metabolism
Nerve Tissue Proteins*
Neurotransmitter Uptake Inhibitors / chemical synthesis*
Neurotransmitter Uptake Inhibitors / chemistry
Neurotransmitter Uptake Inhibitors / metabolism
Norepinephrine / metabolism*
Norepinephrine Plasma Membrane Transport Proteins
Radioligand Assay
Serotonin / metabolism*
Serotonin Plasma Membrane Transport Proteins
Structure-Activity Relationship
Symporters*

Substances

(3-(3,4-dichlorophenyl)-4-methoxyindan-1-yl)methylamine
Carrier Proteins
Dopamine Plasma Membrane Transport Proteins
Indans
Membrane Glycoproteins
Membrane Transport Proteins
Methylamines
Nerve Tissue Proteins
Neurotransmitter Uptake Inhibitors
Norepinephrine Plasma Membrane Transport Proteins
Serotonin Plasma Membrane Transport Proteins
Symporters
Serotonin
indatraline
Dopamine
Norepinephrine