Synthesis and biological evaluation of bupropion analogues as potential pharmacotherapies for cocaine addiction.

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Carroll FI, Blough BE, Abraham P, Mills AC, Holleman JA, Wolckenhauer SA, Decker AM, Landavazo A, McElroy KT, Navarro HA, Gatch MB, Forster MJ

Synthesis and biological evaluation of bupropion analogues as potential pharmacotherapies for cocaine addiction.

J Med Chem. 2009 Nov 12;52(21):6768-81. doi: 10.1021/jm901189z.

PubMed ID

19821577 [ View in PubMed

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Abstract

A series of bupropion (1a) analogues (1b-1ff) were synthesized, and their in vitro and in vivo pharmacological properties evaluated with the goal of developing a 1a analogue that had better properties for treating addictions. Their in vitro pharmacological properties were examined by [(3)H]dopamine ([(3)H]DA), [(3)H]serotonin ([(3)H]5HT), and [(3)H]norepinephrine ([(3)H]NE) uptake inhibition studies, and by binding studies at the dopamine, serotonin, and norepinephrine transporters using [(125)I]RTI-55 in cloned transporters. Several analogues showed increased [(3)H]DA uptake inhibition with reduced or little change in [(3)H]5HT and [(3)H]NE uptake inhibition relative to bupropion. Thirty-five analogues were evaluated in a 1 h locomotor activity observation test and 32 in an 8 h locomotor activity observation test and compared to the locomotor activity of cocaine. Twenty-four analogues were evaluated for generalization to cocaine drug discrimination after i.p. administration, and twelve analogues were tested in a time course cocaine discrimination study using oral administration. 2-(N-Cyclopropylamino)-3-chloropropiophenone (1x) had the most favorable in vitro efficacy and in vivo pharmacological profile for an indirect dopamine agonist pharmacotherapy for treating cocaine, methamphetamine, nicotine, and other drugs of abuse addiction.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Bupropion	Sodium-dependent dopamine transporter	IC 50 (nM)	945	N/A	N/A	Details
Bupropion	Sodium-dependent dopamine transporter	Ki (nM)	871	N/A	N/A	Details
Bupropion	Sodium-dependent noradrenaline transporter	IC 50 (nM)	443	N/A	N/A	Details
Bupropion	Sodium-dependent noradrenaline transporter	Ki (nM)	6970	N/A	N/A	Details