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γ-Aminobutyric Acid Amides of Nortriptyline and Fluoxetine Display Improved Pain Suppressing Activity

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Ada Rephaeli*^†, Irit Gil-Ad^‡, Ana Aharoni^§, Igor Tarasenko^†, Nataly Tarasenko^†, Yona Geffen, Efrat Halbfinger, Yotam Nisemblat, Abraham Weizman^‡ and Abraham Nudelman*^§

Laboratory of Pharmacology and Experimental Oncology and Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv, Israel, Department of Chemistry, Bar Ilan University, Ramat Gan, Israel, and Bioline Innovations Jerusalem LP, 19 Hartum Street, Jerusalem, Israel

J. Med. Chem., 2009, 52 (9), pp 3010–3017

DOI: 10.1021/jm900143u

Publication Date (Web): April 20, 2009

* To whom correspondence should be addressed. For A.R.: (address) Laboratory of Pharmacology and Experimental Oncology, Felsenstein Medical Research Center, Tel-Aviv University, Rabin Medical Center Petah Tikva 49100, Israel; (phone) +972 3 937 6126; (fax) +972 3 922 8096; (e-mail) adarep@post.tau.ac.il. For A.N.: (address) Department of Chemistry, Bar-Ilan University, Ramat Gan 52900, Israel; (phone/fax) +972-3-5318314; (e-mail) nudelman@mail.biu.ac.il., †

Laboratory of Pharmacology and Experimental Oncology, Tel-Aviv University.

, ‡

Laboratory of Biological Psychiatry, Tel-Aviv University.

, §

Bar Ilan University.

Bioline Innovations Jerusalem LP.

Section:

Pharmacology

Abstract

The GABA amides of the antidepressants nortriptyline and fluoxetine, 1 and 2, were compared to their respective parent compounds in rodent models of pain. The amides significantly reduced early nociceptive and late inflammatory responses compared to nortriptyline or fluoxetine, where 1 exhibited overall better efficacy than 2. Amide 1 was most efficacious in lowering cytokine secretion, edema and hyperalgesia induced by formalin and λ-carrageenan, respectively. Thus, 1 is a promising candidate for the treatment of pain.

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Published In Issue May 14, 2009
Article ASAPApril 20, 2009
Received: February 4, 2009

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γ-Aminobutyric Acid Amides of Nortriptyline and Fluoxetine Display Improved Pain Suppressing Activity

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