N-Substituted Benztropine Analogs: Selective Dopamine Transporter Ligands with a Fast Onset of Action and Minimal Cocaine-Like Behavioral Effects

Li, Sumin; Kopajtic, Theresa; O'Callaghan, Matthew J.; Agoston, Gregory E.; Cao, Jianjing; Newman, Amy Hauck; Katz, Jonathan L.

doi:10.1124/jpet.110.173260

Cited by 33 publications

(49 citation statements)

References 37 publications

(40 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Likewise, muscarinic M 2 sites seem improbable, as the BZT-derived atypical DAT inhibitors have a wide variety of reported activity at this site. Notably, the N-substituted BZT analog GA-299 had little cocaine-like activity and lacked affinity for the M 2 muscarinic site (Li et al, 2011). Previous studies have also found inconsistencies in affinities at 5-HT 1 binding sites among N-substituted BZT analogs Li et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…For example, the D 3 R affinity of LX-20, which did not stimulate locomotor activity, was greater than that for LX-19, which did stimulate activity, and greater than its affinity for the DAT, suggesting a role for D 3 Rs in the atypical effects of LX-20. However, Li et al (2011) examined a group of BZT analogs that were considered atypical DAT ligands. Within that group, the compound that was most like cocaine, JHW013, had the greatest affinity for D 3 Rs.…”

Section: Discussionmentioning

confidence: 99%

“…More recently, it has been suggested that compounds with sigma receptor (sR) antagonist effects along with their affinity for the DAT will exhibit atypical DAT inhibitory effects similar to BZT . A number of previous studies indicated that sR antagonists can block several effects of cocaine, including locomotor stimulation, sensitization, and place conditioning (see review by Katz et al, 2011), and it is noteworthy that BZT analogs also have affinity for sRs Li et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

2-Substituted 3β-Aryltropane Cocaine Analogs Produce Atypical Effects without Inducing Inward-Facing Dopamine Transporter Conformations

Hong

Kopajtic

et al. 2016

The Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

Previous structure-activity relationship studies indicate that a series of cocaine analogs, 3b-aryltropanes with 2b-diarylmethoxy substituents, selectively bind to the dopamine transporter (DAT) with nanomolar affinities that are 10-fold greater than the affinities of their corresponding 2a-enantiomers. The present study compared these compounds to cocaine with respect to locomotor effects in mice, and assessed their ability to substitute for cocaine (10 mg/kg, i.p.) in rats trained to discriminate cocaine from saline. Despite nanomolar DAT affinity, only the 2b-Ph 2 COCH 2 -3b-4-ClPh analog fully substituted for cocaine-like discriminative effects. Whereas all of the 2b compounds increased locomotion, only the 2b-(4-ClPh)PhCOCH 2 -3b-4-Cl-Ph analog had cocaine-like efficacy. None of the 2a-substituted compounds produced either of these cocaine-like effects. To explore the molecular mechanisms of these drugs, their effects on DAT conformation were probed using a cysteine-accessibility assay. Previous reports indicate that cocaine binds with substantially higher affinity to the DAT in its outward (extracellular)-compared with inward-facing conformation, whereas atypical DAT inhibitors, such as benztropine, have greater similarity in affinity to these conformations, and this is postulated to explain their divergent behavioral effects. All of the 2b-and 2a-substituted compounds tested altered cysteine accessibility of DAT in a manner similar to cocaine. Furthermore, molecular dynamics of in silico inhibitor-DAT complexes suggested that the 2-substituted compounds reach equilibrium in the binding pocket in a cocaine-like fashion. These behavioral, biochemical, and computational results show that aryltropane analogs can bind to the DAT and stabilize outward-facing DAT conformations like cocaine, yet produce effects that differ from those of cocaine.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

2-Substituted 3β-Aryltropane Cocaine Analogs Produce Atypical Effects without Inducing Inward-Facing Dopamine Transporter Conformations

Hong

Kopajtic

et al. 2016

The Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

show abstract

“…It is well-documented that cocaine's rapid onset of action contributes to its highly-rewarding efficacy and addictive potential (Busto and Sellers, 1986;Kimmel et al, 2008;Kimmel et al, 2007), although not all studies support this view (Li et al, 2011). In rodents, different rates of cocaine delivery affect its addictive liability-drugs reaching the brain rapidly are more addictive than those that reach the brain slowly (Oldendorf, 1992;Samaha and Robinson, 2005;Wakabayashi et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

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

Song²,

et al. 2016

Neuropsychopharmacol

View full text Add to dashboard Cite

Agonist-replacement therapies have been successfully used for treatment of opiate and nicotine addiction, but not for cocaine addiction. One of the major obstacles is the cocaine-like addictive potential of the agonists themselves. We report here an atypical dopamine (DA) transporter (DAT) inhibitor, CTDP-32476, that may have translational potential for treating cocaine addiction. In vitro ligand-binding assays suggest that CTDP-32476 is a potent and selective DAT inhibitor and a competitive inhibitor of cocaine binding to the DAT. Systemic administration of CTDP-32476 alone produced a slow-onset, long-lasting increase in extracellular nucleus accumbens DA, locomotion, and brain-stimulation reward. Drug-naive rats did not self-administer CTDP-32476. In a substitution test, cocaine self-administration rats displayed a progressive reduction in CTDP-32476 self-administration with an extinction pattern of drug-taking behavior, suggesting significantly lower addictive potential than cocaine. Pretreatment with CTDP-32476 inhibited cocaine self-administration, cocaineassociated cue-induced relapse to drug seeking, and cocaine-enhanced extracellular DA in the nucleus accumbens. These findings suggest that CTDP-32476 is a unique DAT inhibitor that not only could satisfy 'drug hunger' through its slow-onset long-lasting DAT inhibitor action, but also render subsequent administration of cocaine ineffectual-thus constituting a novel and unique compound with translational potential as an agonist therapy for treatment of cocaine addiction.

show abstract

“…Thus the slower association rates with DAT might result in a cocaine-antagonist action. However, a study introduced several atypical dopamine uptake inhibitors with fast association rates with DAT in mice [17]. Therefore, it appears that the slower association rates with DAT are not essential for induction of a cocaine-antagonist action, either.…”

Section: Differences In Kinetic Variablesmentioning

confidence: 99%

Cocaine Antagonists; Studies on Cocaine Self-Administration

Hiranita

2015

J Alcohol Drug Depend

View full text Add to dashboard Cite

EditorialA series of recent studies by Dr. Jonathan Katz demonstrated preclinical efficacy of several compounds functioning as a cocaine antagonist using a drug self-administration procedure in rats. For example, 1) the atypical dopamine uptake inhibitors ( Figure 1) JHW 007, AHN 2-005 [1,2], and , and 2) the σ receptor (σR) antagonist (Figure 2) rimcazole and its analogues , all were able to shift dose-effect curves of cocaine self-administration down in a dose-dependent fashion when pre-treated.Their dose-dependent insurmountable antagonism of cocaine self-administration was relatively specific because comparable responding maintained by presentations of food pellets was insensitive to active doses of these compounds that decreased maximal responding maintained by cocaine injection [1][2][3][4]. The pattern of antagonism was similar to effects of the μ-opioid agonist methadone on heroin self-administration since methadone can also produce a dose-dependent insurmountable antagonism of heroin self-administration [5]. On the other hand, none of them maintained self-administration responding above vehicle levels when substituted cocaine [1,3,4], d-methamphetamine, heroin or ketamine [5]. However, the pattern of substitution was different from that of methadone since methadone can substitute for heroin or d-methamphetamine [5]. An excellent review article recently discussed potential mechanisms underlying their action as a cocaine antagonist [6]. There are several relatively viable mechanisms underlying their cocaine-antagonist effect. Dopamine Transporter (DAT)/σ R Dual InhibitionPretreatment with standard dopamine uptake inhibitors alone (Figure 3) shifted the doseeffect curves of cocaine self-administration to the left (i.e. potentiation) in a dose-dependent manner [1,3,4,7,8] while that of σR antagonists was virtually without effects on cocaine selfadministration [4,9-11].However, pretreatment with a σR antagonist dose-dependently shifted down dose-effect curves of cocaine self-administration when combined with a standard dopamine uptake inhibitor [4]. Thus it appears that DAT/σR dual inhibition can result in an insurmountableThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. HHS Public AccessAuthor manuscript J Alcohol Drug Depend. Author manuscript; available in PMC 2016 July 07. Author Manuscript Author ManuscriptAuthor Manuscript Author Manuscriptantagonism of reinforcing effects of cocaine. Interestingly all above-referenced compounds function as a cocaine antagonist except RTI-371, which also have considerable affinity to the DAT as well as σ1Rs (Table 1) relative to the standard dopamine uptake inhibitors except RTI-336.However, the atypical dopamine uptake inhibitor RTI-371 and the standard dopamine uptake inhibitor RTI-336 both commonly have high affinity to the DAT as well as σ2Rs, and low affinity to σ1Rs (Table 1) ...

show abstract

N-Substituted Benztropine Analogs: Selective Dopamine Transporter Ligands with a Fast Onset of Action and Minimal Cocaine-Like Behavioral Effects

Cited by 33 publications

References 37 publications

2-Substituted 3β-Aryltropane Cocaine Analogs Produce Atypical Effects without Inducing Inward-Facing Dopamine Transporter Conformations

2-Substituted 3β-Aryltropane Cocaine Analogs Produce Atypical Effects without Inducing Inward-Facing Dopamine Transporter Conformations

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

Cocaine Antagonists; Studies on Cocaine Self-Administration

Contact Info

Product

Resources

About