Further studies on conformationally constrained tricyclic tropane analogues and their uptake inhibition at monoamine transporter sites: Synthesis of (z)-9-(substituted arylmethylene)-7-azatricyclo[4.3.1.03,7]decanes as a Novel class of serotonin transporter inhibitors

Ao Zhang, Guochun Zhou, Alexander Hoepping, Jayanta Mukhopadhyaya, Kenneth M. Johnson, Mei Zhang, Alan P. Kozikowski

Research output: Contribution to journalArticle

Abstract

A novel series of conformationally constrained tricyclic tropane analogues, (Z)-9-(substituted arylmethylene)-7-azatricyclo[4.3.1.03,7]decanes, were prepared, and their abilities to inhibit high-affinity uptake of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) into rat brain nerve endings (synaptosomes) were evaluated. First, a systematic screening of a variety of different substituents on the phenyl ring indicated that the substitution pattern plays an important role in the monoamine transporter activity. Most compounds in this series possessed a very low activity at the DA transporter (DAT) but a good to excellent affinity for the 5-HT transporter (SERT). In the case of para-substituted phenyl analogues, the electronic character of the substituent did not affect uptake inhibition as dramatically as observed in some benztropine analogues. Among these compounds, the 4-bromophenyl and 4-isopropylphenyl analogues 8d and 8j exhibited the highest potency at the SERT with a Ki value of 10 nM. In the 3,4-disubstituted phenyl series, even more potent and highly selective compounds were discovered. Compound 8o has a Ki value of 2.3 nM for uptake inhibition at the SERT, a DAT/ SERT uptake ratio of 2360, and a NET/SERT uptake ratio of 200. Compound 8p exhibited a Ki value of 1.8 nM for uptake inhibition at the SERT, a DAT/SERT uptake ratio of 1740, and a NET/SERT uptake ratio of 151. These compounds are 3-4-fold more potent than the antidepressant medication fluoxetine, and the selectivities for SERT over DAT and NET are also better than those of fluoxetine. Second, a variety of functional modifications on the ester moiety were investigated. Substitution by other esters or amides as well as alkenes did not increase potency, while most of the acetates or benzoates (16-21, 23, and 24) and the ketone 28 exhibited significantly improved activity. A good hydrogen-bonding ability of the substituent is believed to be required for high activity. The most potent and selective ligand is compound 23, which displayed a Ki value of 0.06 nM and has essentially no activity at the DAT or NET. The present results have important implications for drug addiction as well as a number of psychiatric diseases.

Original languageEnglish (US)
Pages (from-to)1930-1941
Number of pages12
JournalJournal of Medicinal Chemistry
Volume45
Issue number9
DOIs
StatePublished - Apr 25 2002
Externally publishedYes

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Tropanes
Serotonin Plasma Membrane Transport Proteins
Serotonin
Aptitude
Fluoxetine
Esters
Substitution reactions
Benztropine
Dopamine Plasma Membrane Transport Proteins
Nerve Endings
Synaptosomes
Benzoates
Alkenes
Hydrogen Bonding
Ketones
Amides
Antidepressive Agents
Substance-Related Disorders
Psychiatry
Rats

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Further studies on conformationally constrained tricyclic tropane analogues and their uptake inhibition at monoamine transporter sites : Synthesis of (z)-9-(substituted arylmethylene)-7-azatricyclo[4.3.1.03,7]decanes as a Novel class of serotonin transporter inhibitors. / Zhang, Ao; Zhou, Guochun; Hoepping, Alexander; Mukhopadhyaya, Jayanta; Johnson, Kenneth M.; Zhang, Mei; Kozikowski, Alan P.

In: Journal of Medicinal Chemistry, Vol. 45, No. 9, 25.04.2002, p. 1930-1941.

Research output: Contribution to journalArticle

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T2 - Synthesis of (z)-9-(substituted arylmethylene)-7-azatricyclo[4.3.1.03,7]decanes as a Novel class of serotonin transporter inhibitors

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AU - Zhou, Guochun

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AU - Kozikowski, Alan P.

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