A slow-onset, long-duration indanamine monoamine reuptake inhibitor as a potential maintenance pharmacotherapy for psychostimulant abuse: Effects in laboratory rat models relating to addiction

CTDP-32476: A Promising Agonist Therapy for Treatment of Cocaine Addiction

“…Similarly, in humans, the more rapidly cocaine (Volkow et al, 2000) or methylphenidate (Volkow et al, 2002) enters the brain, the greater the reported 'high'. On the basis of this, we previously proposed that slowonset long-acting MAT or DAT inhibitors should have lower addictive potential than cocaine (Froimowitz et al, 2000(Froimowitz et al, , 2007Gardner et al, 2006;Peng et al, 2010). In the present study, multiple lines of evidence demonstrate that CTDP-32476 is an exceptional slow-onset (20-60 min) long-duration (6-12 h) DAT inhibitor that displays significantly lower addiction potential than cocaine.…”

“…Cocaine's addictive properties are believed to be mediated predominantly by blockade of presynaptic DA transport (DAT; Wise, 1996). It has therefore been proposed that a MAT or DAT inhibitor may act as a substitute for cocaine in drug-dependent individuals (Gardner et al, 2006;Gorelick et al, 2004;Grabowski et al, 2004;Runyon and Carroll, 2006). A conceptually similar approach has proven effective for opiate addiction (using methadone as the substitute opiate) and for smoking cessation (using varenicline or nicotine to substitute for tobacco-derived nicotine) in a subpopulation of addicts (Gerra et al, 2009;Silagy et al, 2004).…”

“…Given that methadone is a relatively long-acting opioid receptor agonist and nicotine-replacement therapies have slow-release as a feature, we proposed that a MAT or DAT inhibitor with a slow-onset, long-acting profile might have potential as an agonist therapy for treating cocaine addiction (Froimowitz et al, 2000;Gardner et al, 2006;Peng et al, 2010). However, the tested compounds in those studies were nonselective MAT inhibitors, which displayed high psychomotor-stimulation and functionally enhanced cocaine's action on extracellular DA and brain-stimulation reward (BSR, Gardner et al, 2006;Peng et al, 2010), suggesting that MAT inhibitors with slow-onset long-lasting profiles have less than desirable therapeutic potential.…”

“…However, the tested compounds in those studies were nonselective MAT inhibitors, which displayed high psychomotor-stimulation and functionally enhanced cocaine's action on extracellular DA and brain-stimulation reward (BSR, Gardner et al, 2006;Peng et al, 2010), suggesting that MAT inhibitors with slow-onset long-lasting profiles have less than desirable therapeutic potential. Several other ligands such as GBR-12909, PTT [2β-propanoyl-3β-(4-tolyl)-tropane], and RTI (Research Triangle Institute) compounds (3-phenyltropane analogs) have been previously thought to be 'slow-onset long-acting' DAT inhibitors (Howell and Wilcox, 2001;Rothman et al, 2008).…”

Antidepressant-Like Pharmacological Profile of a Novel Triple Reuptake Inhibitor, (1S,2S)-3-(Methylamino)-2-(naphthalen-2-yl)-1-phenylpropan-1-ol (PRC200-SS)

“…The slow onset and long-lasting reduction in extracellular monoamine metabolites associated with the increase in extracellular NE, DA, and 5-HT after PRC200-SS administration was also observed with another triple reuptake inhibitor, DOV 102,677 (Popik et al, 2006), the SSRI fluoxetine (Clark et al, 1996), and other monoamine uptake blockers (Gardner et al, 2006), suggesting that it might be a common property of monoamine transporter inhibitors. These results are totally consistent with the action of transporter-blocking drugs and with our understanding of the metabolism of catecholamines and 5-HT by intracellular enzymes.…”