Potent Dopamine Uptake Inhibitor Research Articles

Rigid Adenine Nucleoside Derivatives as Novel Modulators of the Human Sodium Symporters for Dopamine and Norepinephrine.

Thirty-two congeneric rigid adenine nucleoside derivatives containing a North (N)-methanocarba ribose substitution and a 2-arylethynyl group either enhanced (up to 760% of control) or inhibited [(125)I] methyl (1R,2S,3S)-3-(4-iodophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate (RTI-55) binding at the human dopamine (DA) transporter (DAT) and inhibited DA uptake. Several nucleosides also enhanced [(3)H]mazindol [(±)-5-(4-chlorophenyl)-3,5-dihydro-2H-imidazo[2,1-a]isoindol-5-ol] binding to the DAT. The combination of binding enhancement and functional inhibition suggests possible allosteric interaction with the tropanes. The structure-activity relationship of this novel class of DAT ligands was explored: small N(6)-substition (methyl or ethyl) was favored, while the N1 of the adenine ring was essential. Effective terminal aryl groups include thien-2-yl (compounds 9 and 16), with EC50 values of 35.1 and 9.1 nM, respectively, in [(125)I]RTI-55 binding enhancement, and 3,4-difluorophenyl as in the most potent DA uptake inhibitor (compound 6) with an IC50 value of 92 nM (3-fold more potent than cocaine), but not nitrogen heterocycles. Several compounds inhibited or enhanced binding at the norepinephrine transporter (NET) and serotonin transporter (SERT) and inhibited function in the micromolar range; truncation at the 4'-position in compound 23 allowed for weak inhibition of the SERT. We have not yet eliminated adenosine receptor affinity from this class of DAT modulators, but we identified modifications that remove DAT inhibition as an off-target effect of potent adenosine receptor agonists. Thus, we have identified a new class of allosteric DAT ligands, rigidified adenosine derivatives, and explored their initial structural requirements. They display a very atypical pharmacological profile, i.e., either enhancement by increasing affinity or inhibition of radioligand binding at the DAT, and in some cases the NET and SERT, and inhibition of neurotransmitter uptake.

Effects of the histamine H1 receptor antagonist and benztropine analog diphenylpyraline on dopamine uptake, locomotion and reward

Diphenylpyraline hydrochloride (DPP) is an internationally available antihistamine that produces therapeutic antiallergic effects by binding to histamine H1 receptors. The complete neuropharmacological and behavioral profile of DPP, however, remains uncharacterized. Here we describe studies that suggest DPP may fit the profile of a potential agonist replacement medication for cocaine addiction. Aside from producing the desired histamine reducing effects, many antihistamines can also elicit psychomotor activation and reward, both of which are associated with increased dopamine concentrations in the nucleus accumbens (NAc). The primary aim of this study was to investigate the potential ability of DPP to inhibit the dopamine transporter, thereby leading to elevated dopamine concentrations in the NAc in a manner similar to cocaine and other psychostimulants. The psychomotor activating and rewarding effects of DPP were also investigated. For comparative purposes cocaine, a known dopamine transporter inhibitor, psychostimulant and drug of abuse, was used as a positive control. As predicted, both cocaine (15mg/kg) and an equimolar dose of DPP (14mg/kg) significantly inhibited dopamine uptake in the NAc in vivo and produced locomotor activation, although the time-course of pharmacological effects of the two drugs was different. In comparison to cocaine, DPP showed a prolonged effect on dopamine uptake and locomotion. Furthermore, cocaine, but not DPP, produced significant conditioned place preference, a measure of drug reward. The finding that DPP functions as a potent dopamine uptake inhibitor without producing significant rewarding effects suggests that DPP merits further study as a potential candidate as an agonist pharmacotherapy for cocaine addiction.

Nomifensine: a new potent inhibitor of dopamine uptake into synaptosomes from rat brain corpus striatum.

Nomifensine: a new potent inhibitor of dopamine uptake into synaptosomes from rat brain corpus striatum.

A dopamine transport inhibitor with markedly low abuse liability suppresses cocaine self-administration in the rat

N-substituted benztropine analogs are potent dopamine uptake inhibitors that display pharmacokinetic/dynamic properties consistent with the profile of a substitute medication for cocaine addiction. The purpose of the present experiments was to characterize in rats the addictive-like properties of one such analog, 3 alpha-[bis(4'-fluorophenyl)methoxy]-tropane (AHN-1055), incorporating probes of its stimulant and incentive/motivational effects and of its ability to influence cocaine self-administration. We used open field activity and drug self-administration assays. To examine the effects of AHN-1055 on locomotor behavior, the analog was administered alone (0, 1, 3, and 10 mg/kg intraperitoneally) and in combination with cocaine (15 mg/kg i.p.). The influence of AHN-1055 on cocaine's intake was studied by administering the analog (0, 3, and 10 mg/kg i.p.) before the start of the self-administration sessions. To compare the addictive-like properties of AHN-1055 and cocaine, progressive ratio performance and abstinence-induced context-conditioned relapse were evaluated. AHN-1055 evoked robust and sustained locomotor activity when administered alone and increased cocaine-induced locomotor stimulation. Notably, the analog showed by comparison to cocaine weak reinforcing efficacy in a modified progressive ratio schedule of drug reinforcement, and contrary to cocaine, it showed no ability to promote context-conditioned relapse to drug seeking following stable self-administration and abstinence. Further, AHN-1055 treatment blocked cocaine intake dose-dependently in rats with a steady history of cocaine self-administration without reducing responding for sucrose, a natural reward. These findings demonstrate essential psychopharmacological differences between AHN-1055 and cocaine and highlight important properties of the analog as a possible pharmacotherapy in cocaine addiction.

Local noradrenaline depletion elicits enhanced dopamine activity in the medial prefrontal cortex

Event Abstract Back to Event Local noradrenaline depletion elicits enhanced dopamine activity in the medial prefrontal cortex Rita Galosi1*, Attila Toth1, Zoltan Petyko1 and László Lénárd1 1 Hungarian Academy of Sciences , Medical School of University Pecs, Hungary Earlier data showed coupling between dopamine (DA) and noradrenaline (NA) release in the prefrontal cortex. In the present experiments, bilateral neurochemical lesions were carried out to destroy NA terminals in the medial prefrontal cortex (mPFC). In loco injection of 6-hydroxy-DOPA (6-OHDOPA) was applied. In other group, a potent DA uptake inhibitor, GBR12935 was injected before the administration of neurotoxin 6-hydroxy-dopamine (6-OHDA), which acts on both DA and NA terminal. DA and NA contents of the mPFC were determined by HPLC-electrochemical detection post mortem and in vivo. In controls, NA and DA values were 346.21 +/- 36.02 ng/g and 133.29 +/-21.61 ng/g wet weight tissue (average ± s.e.m.), respectively. GBR 12935 treatment alone did not show significant alteration in catecholamine levels. Lesions of NA terminals by 6-OHDOPA depleted the NA level only by 21 % [p<0.05]. 6-OHDOPA lesion caused elevated DA levels by 122 % [p<0.01]. Concentration of NA was reduced by 43 % [p<0.01] do to GBR 12935 + 6-OHDA lesion. The DA levels were elevated in these cases by 195 % [p<0.01]. Extracellular NA and DA concentrations were 4.36 +/- 1.03 and 5.32 +/- 0.7 pg/20μl sample, respectively. NA concentration was no detectable after GBR 12935 + 6-OHDA lesion. Baseline DA concentrations were enhanced [p<0.05]. Local reverse microdialysis of Yohimbine (10μM) α2 antagonist enhanced NA and DA level in the mPFC. Increase in DA concentration was higher following neurochemical lesion of NA terminals [p<0.01]. In summary, decreased NA input enhanced DA activity in the mPFC. This study was supported by ETT 317/2006, NKTH-OTKA K68431 and by the Hungarian Academy of Sciences. Conference: 12th Meeting of the Hungarian Neuroscience Society, Budapest, Hungary, 22 Jan - 24 Jan, 2009. Presentation Type: Poster Presentation Topic: Research on the cerebral cortex and related structures Citation: Galosi R, Toth A, Petyko Z and Lénárd L (2009). Local noradrenaline depletion elicits enhanced dopamine activity in the medial prefrontal cortex. Front. Syst. Neurosci. Conference Abstract: 12th Meeting of the Hungarian Neuroscience Society. doi: 10.3389/conf.neuro.01.2009.04.193 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 06 Mar 2009; Published Online: 06 Mar 2009. * Correspondence: Rita Galosi, Hungarian Academy of Sciences , Medical School of University Pecs, Pecs, Hungary, rita.galosi@aok.pte.hu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Rita Galosi Attila Toth Zoltan Petyko László Lénárd Google Rita Galosi Attila Toth Zoltan Petyko László Lénárd Google Scholar Rita Galosi Attila Toth Zoltan Petyko László Lénárd PubMed Rita Galosi Attila Toth Zoltan Petyko László Lénárd Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

3-{2-[Bis-(4-fluorophenyl)methoxy]ethyl}-6-substituted-3,6-diazabicyclo[3.1.1]heptanes as novel potent dopamine uptake inhibitors

A series of analogues 2a– i related to 3-{2-[bis-(4-fluorophenyl)methoxy]ethyl}-8-(1 H-indol-2-ylmethyl)-3,8-diazabicyclo[3.2.1]octane ( 1) in which the 3,8-diazabicyclo[3.2.1]octane core was replaced by 3,6-diazabicyclo[3.1.1]heptane ring system has been synthesized and evaluated for their ability to inhibit DA reuptake into striatal nerve endings (synaptosomes). Biological data showed that compound 2a, the closest analogue of lead 1, possessed an increased reuptake inhibition activity over 1 ( 2a, K i = 5.5 nM). Replacement of the indole ring with bioisosteric aromatic rings—benzothiophene ( 2b), benzofurane ( 2c), or indene ( 2d)—resulted, with the exception of 2d, in a double digit nanomolar activity. Changing the indenyl moiety of 2d with simplified aryl groups led to compounds 2e– h which displayed a similar or slightly decreased activity with respect to the ground term. Naphthalene derivative ( 2i) demonstrated a weaker activity than aromatic analogues.

Development of the dopamine transporter selective RTI-336 as a pharmacotherapy for cocaine abuse

The discovery and preclinical development of selective dopamine reuptake inhibitors as potential pharmacotherapies for treating cocaine addiction are presented. The studies are based on the hypothesis that a dopamine reuptake inhibitor is expected to partially substitute for cocaine, thus decreasing cocaine self-administration and minimizing the craving for cocaine. This type of indirect agonist therapy has been highly effective for treating smoking addiction (nicotine replacement therapy) and heroin addiction (methadone). To be an effective pharmacotherapy for cocaine addiction, the potential drug must be safe, long-acting, and have minimal abuse potential. We have developed several 3-phenyltropane analogs that are potent dopamine uptake inhibitors, and some are selective for the dopamine transporter relative to the serotonin and norepinephrine transporters. In animal studies, these compounds substitute for cocaine, reduce the intake of cocaine in rats and rhesus monkeys trained to self-administer cocaine, and have demonstrated a slow onset and long duration of action and lack of sensitization. The 3-phenyltropane analogs were also tested in a rhesus monkey self-administration model to define their abuse potential relative to cocaine. Based on these studies, 3beta-(4-chlorophenyl)-2beta-[3-(4'-methylphenyl)isoxazol-5-yl]tropane (RTI-336) has been selected for preclinical development.

Structure-activity relationships at monoamine transporters for a series of N-substituted 3alpha-(bis[4-fluorophenyl]methoxy)tropanes: comparative molecular field analysis, synthesis, and pharmacological evaluation.

The development of structure-activity relationships (SAR) with divergent classes of monoamine transporter ligands and comparison of their effects in animal models of cocaine abuse have provided insight into the complex relationship among structure, binding profiles, and behavioral activity. Many 3alpha-(diphenylmethoxy)tropane (benztropine) analogues are potent dopamine uptake inhibitors but exhibit behavioral profiles that differ from those of cocaine and other compounds in this class. One of the most potent and dopamine transporter (DAT) selective N-substituted benztropine analogues (N-(4-phenyl-n-butyl)-3alpha-(bis[4-fluorophenyl]methoxy)tropane, 1c) is devoid of cocaine-like behaviors in rodent models but is also highly lipophilic (cLogD = 5.01), which compromises its water solubility and may adversely affect its pharmacokinetic properties. To further explore the SAR in this series and ultimately to design dopamine uptake inhibitors with favorable lipophilicities for drug development, a comparative molecular field analysis (CoMFA) was performed on a set of benztropine analogues previously synthesized in our laboratory. The CoMFA field analysis on the statistically significant (r2(cv) = 0.632; r2(ncv) = 0.917) models provided valuable insight into the structural features required for optimal binding to the DAT, which was used to design a series of novel benztropine analogues with heteroatom substitutions at the tropane N-8. These compounds were evaluated for binding at DAT, serotonin (SERT) and norepinephrine (NET) transporters, and muscarinic M1 receptors in rat brain. Inhibition of [3H]DA uptake in synaptosomes was also evaluated. Most of the analogues showed high DAT affinity (12-50 nM), selectivity (10- to 120-fold), potent inhibition of dopamine uptake, and lower lipophilicities as predicted by cLogD values.

Efficient asymmetric syntheses, determination of absolute configurations and biological activities of 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(phenylamino)propyl]piperazine as a novel potent dopamine uptake inhibitor in the central nervous system

An efficient asymmetric synthesis of the chiral N-(3-chloro-2-hydroxypropyl)anilines ( 2a and 2b) was achieved through the regioselective ring-opening reaction of chiral epichlorohydrin with aniline. This was applied to an asymmetric synthesis of the enantiomers of 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(phenylamino)propyl]piperazine 1 as a novel potent dopamine uptake inhibitor. Both enantiomers as trihydrochlorides, 4a·3HCl and 4b·3HCl, could be synthesized in good total yields and optical purities of 100% ee in three steps synthesis, respectively. The absolute configurations of 4a·3HCl and 4b·3HCl were determined using the modified Mosher's method with the related compounds, the intermediates ( 2a and 2b) and the free bases ( 4a and 4b). The analytical results indicated that 4a·3HCl and 4b·3HCl have the ( S)- and ( R)-configuration, respectively, and a series of reactions to provide them proceeded without the apparent influence on the stereochemistry at the chiral centers. In in vitro pharmacological evaluations, 4a·3HCl and 4b·3HCl showed potent dopamine transporter binding affinities, high dopamine, moderate serotonin, and weak norepinephrine uptake inhibitory activities, and 4a·3HCl exhibited a more potent and selective dopamine uptake inhibition over the serotonin or norepinephrine uptake inhibition as compared with 4b·3HCl. An ex vivo evaluation revealed that the oral administrations of both enantiomers at a dose of 30 mg/kg in rats displayed apparent dopamine uptake inhibitory activities and 4a·3HCl had a stronger tendency to inhibit dopamine uptake compared with 4b·3HCl.

Synthesis, Lipophilicity and Structure of 2,5‐Disubstituted 1,3,5‐Dithiazine Derivatives.

AbstractFor Abstract see ChemInform Abstract in Full Text.

(−)-Deprenyl inhibits tyramine-induced noradrenaline release, but not tyramine-induced dopamine release or potassium-induced noradrenaline release, from rat brain synaptosomes

The effect of (−)-deprenyl (selegiline), a therapeutic agent for Parkinson’s disease, on the tyramine-induced release of catecholamine from rat brain synaptosomes was studied using a superfusion system. Tyramine (10 −7 to 10 −5 M) enhanced the release of [ 3 H] noradrenaline (NA) and [ 3 H] dopamine (DA) from forebrain and striatal synaptosomes in a dose-dependent manner. (−)-Deprenyl (5×10 −5 M) had no effect on spontaneous catecholamine release, suggesting that it has no tyramine-like catecholamine releasing effect. Pretreatment with (−)- or (+)-deprenyl (5×10 −5 M) significantly prevented the tyramine (10 −6 M)-induced NA release, but not DA release. The inhibitory action of (−)-deprenyl was not observed on potassium (15 mM)-induced NA release. (−)-Desmethyldeprenyl (5×10 −5 M), a metabolite of (−)-deprenyl, and a monoamine oxidase-A (MAO-A) inhibitor, clorgyline (5×10 −5 M), failed to block the tyramine-induced NA and DA release. Although (+)-deprenyl, a potent DA uptake inhibitor, did not inhibit tyramine-induced DA release, a catecholamine uptake inhibitor nomifensine (5×10 −5 M) did. In summary, (−)-deprenyl at a dose inhibiting tyramine-induced NA release did not have any effect on tyramine-induced DA release or potassium-induced NA release.

Synthesis, lipophilicity and structure of 2,5‐disubstituted 1, 3, 5‐dithiazine derivatives

AbstractA series of 2,5‐disubstituted 1,3,5‐dithiazine derivatives were synthesized as potential analogues of the potent dopamine uptake inhibitor GBR 12909. The lipophilic character of the 1,3,5‐dithiazine derivatives were experimentally (log P) and computationally (clog P) determined. The in vitro binding affinities of the 2,5‐disubstituted 1,3,5‐dithiazine derivatives at the dopamine transporter were determined to be much less potent than the binding affinity of GBR 12909 due to steric and electronic effects inherent to the 1,3,5‐dithiazine ring system. The X‐ray crystal structure of 2‐(2‐[bis(4‐fluorophenyl)methoxy]ethyl)‐5‐(3‐phenylpropyl)‐1,3,5‐dithiazine (7) revealed that the 5‐(3‐phenylpropyl) group is in a pseudo‐axial orientation and syn to the 2‐ethoxybenzhydryl moiety.

Novel diphenylalkyl piperazine derivatives with high affinities for the dopamine transporter

The novel diphenyl piperazine derivatives containing the phenyl substituted aminopropanol moiety, including 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(phenylamino)propyl]piperazine 1, which were modified at the connective between the diphenyl and piperazine moieties, have been found to be potent dopamine uptake inhibitors. To study the further structure–activity relationship (SAR) of these compounds, a new series was synthesized, with modifications at the 2-hydroxy-3-phenylaminopropyl moiety of 1. The series was evaluated for dopamine transporter (DAT) binding affinity with [ 3H]GBR12935 in rat striatal membranes. Most of the compounds showed moderate to high DAT binding affinities and some were approximately equivalent in activity to compound 1 or GBR12909 as a dopamine uptake inhibitor, with IC 50 values of nanomolar range. The SAR suggested that on exhibiting a potent interaction with the DAT, there is probably a steric limitation around the benzene ring of the phenylamino moiety of 1, allowing only small-sized substituents with the exception of basic moieties at the 4-position. In addition, the SAR at the 3-amino-2-propanol moiety of 1 suggested that either the nitrogen atom with an electron donating substituent or the unsubstituted nitrogen atom and also the hydroxy group are desirable for elicitation of a potent DAT binding affinity.

Syntheses of Novel Diphenyl Piperazine Derivatives and Their Activities as Inhibitors of Dopamine Uptake in the Central Nervous System

A new series of diphenyl piperazine derivatives containing the phenyl substituted aminopropanol moiety, which were modified at sites between the diphenyl and piperazine moieties, was prepared and evaluated for dopamine transporter binding affinity with [ 3H]GBR12935 in rat striatal membranes. These synthesized compounds showed apparent dopamine transporter binding affinities (IC 50<30 nM) and some of them were approximately equivalent in activity to GBR12909 known as a potent dopamine uptake inhibitor, showing the activities with IC 50 values of nanomolar range. Among them, 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(phenylamino)propyl]piperazine 2 was evaluated for extracellular dopamine levels in rat striatum using in vivo brain microdialysis. The intraperitoneal administration of 2 (0.01, 0.03, or 0.1 mmol/kg) induced dose-dependent increases of dopamine levels in rat striatal dialysates. The maximum increases in dopamine levels induced by 2 were greater than those by GBR12909. The pharmacological data of these novel diphenyl piperazine derivatives show that the compounds have potent dopamine uptake inhibitory activities in the central nervous system.

Astroglial dopamine transport is mediated by norepinephrine transporter.

The aim of this study was to clarify the characteristics of the dopamine (DA) transport mechanism in cultured rat cortical astrocytes. Reverse transcription-polymerase chain reaction (RT-PCR) with DA transporter (DAT)-, norepinephrine (NE) transporter (NET)- and organic cation transporter 3 (OCT3)-specific primers demonstrated that rat cortical astrocytes and frontal cortex expressed DAT, NET and OCT3 mRNA. Specific [(3)H]DA and [(3)H]NE uptake were each partly inhibited by 1 micro M decynium 22, an extraneuronal monoamine transporter (EMT) and OCT inhibitor. The selective NE uptake inhibitor nisoxetine (0.1 micro M) and the tricyclic antidepressant desipramine (1 micro M) very potently inhibited the specific uptake of both [(3)H]DA and [(3)H]NE in astrocytes. In contrast, 0.1 micro M GBR-12935, a selective and potent DA uptake inhibitor, had no inhibitory activity on the uptake of either compound. These results suggest that cortical astrocytes regulate extracellular DA and NE concentrations through the uptake of DA and NE by the glial NET but not by DAT. Furthermore, an uptake(2) mechanism contributes to DA uptake in cortical astrocytes.

Effects of haloperidol metabolites on neurotransmitter uptake and release: possible role in neurotoxicity and tardive dyskinesia

This research explored the effects of haloperidol (HP) metabolites on biogenic amine uptake and release, and compared them to those of MPTP and its toxic metabolite, MPP +. In synaptosome preparations from mouse striatum and cortex, the HP metabolites haloperidol pyridinium (HPP +), reduced haloperidol pyridinium (RHPP +), and haloperidol tetrahydropyridine (HPTP) inhibited the presynaptic uptake of dopamine and serotonin, with greater affinity for the serotonin transporter. HPP + was the most potent inhibitor of dopamine uptake, and HPTP of serotonin uptake, both with IC 50 values in the low micromolar range. RHPP + was less active than the other metabolites, but was more active than the parent compound, HP. Inhibition of uptake was reversed when free drug was removed by centrifugation and then resuspension of the synaptosomes in fresh buffer, suggesting that inhibition of uptake was due to interaction with the transporters and was not due to irreversible cytotoxicity. HPP + showed noncompetitive inhibition of both serotonin and dopamine uptake, suggesting that it has a relatively slow dissociation rate for its interaction with the transporter proteins. In experiments on amine release, HPP + and HPTP were four-fold less potent than MPP + for releasing preloaded dopamine from striatal synaptosomes, and only MPP +-dependent release was antagonized by the uptake blocker, mazindol. In contrast, RHPP + displayed little ability to release either amine neurotransmitter. HPTP was about two-fold more potent than MPP + for releasing serotonin from cortical synaptosomes, whereas HPP + was less active than MPP +. The specific serotonin transport blocker fluoxetine was only able to antagonize release induced by MPP +. These results suggest that HP metabolites bind to the transporters for dopamine and serotonin, but are not transporter substrates. In contrast to their potent effects on amine release, HPP + and HPTP were unable to release preloaded GABA from cortical synaptosomes. The implications of these results concerning a possible role of HP metabolites in the development of tardive dyskinesia are discussed.

Novel 4'-substituted and 4',4"-disubstituted 3 alpha-(diphenylmethoxy)tropane analogs as potent and selective dopamine uptake inhibitors.

A series of 4'-substituted and 4',4"-disubstituted 3 alpha-(diphenylmethoxy)tropane analogs were prepared as novel probes for the dopamine transporter. These compounds were evaluated in radiolabeled binding assays for the dopamine, norepinephrine, and serotonin transporters. All of these compounds monophasically displaced [3H]WIN 35,428 binding in rat caudate putamen with Ki values ranging from 11.8 to 2000 nM. The most potent compound in this series was 4',4"-difluoro 3 alpha-(diphenylmethoxy)tropane 7c with a Ki = 11.8 nM. All of the compounds inhibited dopamine uptake in rat caudate putamen (IC50 = 24-4456 nM) which correlated significantly (r = 0.907; p > 0.0001) with binding affinities at the dopamine transporter. None of the compounds demonstrated high-affinity binding at the norepinephrine (Ki > 4800 nM) or serotonin (Ki > 690 nM) transporters. Therefore, the most potent dopamine uptake inhibitors in this series were highly selective for the dopamine transporter. Preliminary behavioral studies of several of these analogs (7a-e) suggested that the compounds did not display a cocaine-like behavioral profile, despite their ability to inhibit dopamine uptake. The present data coupled with the observed differences from cocaine in structure-activity relationships suggested that the 3 alpha-(diphenylmethoxy)tropane analogs may be interacting at a different active site than cocaine on the dopamine transporter and that an additional binding domain might be exploited for the identification of potential therapeutics for the treatment of cocaine abuse.

Dopamine uptake inhibitory activity of novel tryptamine 5‐HT1 receptor ligands

AbstractIn the search for novel serotonin receptor ligands, a series of 5‐thiazolyl‐N,N‐dimethyltryptamine derivatives was synthesized which exhibited high affinity binding to 5‐HT1A, 5‐HT1B, and 5‐HT1D receptors and the functional characteristics of receptor agonists. One member, 5‐(4‐anilnomethyl‐2‐thiazolyl)‐N,N‐dimethyltryptamine (CP‐110,330), was found also to be a potent and selective inhibitor of dopamine uptake in rat striatal synaptosomes. This activity was confirmed by its potent displacement of [3H]N(1‐[2‐benzo(b)thiophenyl]cyclohexyl piperidine (BTCP) binding to the dopamine transporter in striatal membranes. A limited structure‐activity study indicated that optimal dopamine uptake blocking activity was obtained when the thiazole C4 substituent consisted of phenyl with a 2‐atom spacer. The potent effect of these 5‐HT1 receptor ligands on dopamine uptake can be rationalized by the observation that the flexibility of these tryptamine molecules allows the superimposition of the phenyl ring and amino group of the side chain with the corresponding moieties of tametraline, a known catecholamine uptake inhibitor of fixed conformation. A related compound, 3‐(R‐N‐methyl‐2‐pyrrolidinylmethyl)‐5‐(4‐benzyl‐2‐thiazolylamino)‐1H‐indole (CP‐146,662) showed similar potent binding affinity to 5‐HT1 receptors and the dopamine transporter. Compounds with this dual serotonergic and dopaminergic activity may have utility as antidepressant agents. As potent dopamine uptake inhibitors, they may also have application in the treatment of cocaine addiction. © 1994 Wiley‐Liss, Inc.

Quantitative Structure-Activity Relationships for Substituted Aminotetralin Analogues. II: Inhibition of Dopamine Uptake

Quantitative structure-activity relationships of 44 substituted aminotetralin analogues with regard to dopamine (DA) uptake inhibitory potency are examined in this study. Lipophilic substituents at R3 and hydrophilic substituents at Rfi and/or R9 positions, as well as the overall lipophiiicity of the molecule contribute toward increasing the inhibitory potency. Unlike with norepinephrine uptake inhibition, little effects are seen from the nitrogen substituent. Among the ring substituents examined, an hydroxy group at the R6 position increases the DA uptake inhibitory potency, whereas a methoxy group at the R7 position decreases it. A comparative quantitative structure-activity relationship study shows that a bromine at the R6 position and/or hydrogen at the R9position make the compound a better norepinephrine uptake inhibitor than a DA uptake inhibitor, whereas hydrogen at the R6 and/or a substituent larger than a propyl group at the R2 position make the compound a more potent DA uptake inhibitor.

Prenatal exposure to cocaine I: Effects on gestation, development, and activity in Sprague-Dawley rats

Spermpositive Sprague-Dawley rats received one of four treatments for 20 days beginning within 24 hours of conception. One group received subcutaneous injections of 15 mg/kg cocaine twice daily (Cocaine-D); a second group received 15 mg/kg cocaine twice daily for two consecutive days at 5-day intervals (Cocaine-I); a third group received normal saline twice daily (Saline); and a fourth group received 1.5 mg/kg amfonelic acid (AFA), a dopamine reuptake inhibitor, once daily. Cocaine-D, Cocaine-I, and AFA dams were fed ad lib. An attempt was made to pair-feed the Saline dams with the Cocaine-D dams; however, the Saline dams did not eat as much as the Cocaine-D dams which resulted in dams in all groups essentially eating ad lib. The Cocaine-D pups showed a slightly delayed righting behavior and neophobia at 30 days of age, as evidenced by hypoactivity during the first 15 min of a 6-h activity test. The Cocaine-I pups were hypoactive during the 3-h dark phase of the 6-h activity test when tested at 30 days of age. These effects did not occur in the offspring exposed to AFA, a potent dopamine uptake inhibitor and CNS stimulant which indicate that one or more other sites for cocaine action may combine for its effects on the developing fetus.