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Results for “Tropanes”

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At least 19 recordsLinked to original sources

PubMed2003

Structure-activity relationship comparison of (S)-2beta-substituted 3alpha-(bis[4-fluorophenyl]methoxy)tropanes and (R)-2beta-substituted 3beta-(3,4-dichlorophenyl)tropanes at the dopamine transporter.

Extensive structure-activity relationships at the dopamine transporter (DAT) have been developed around two classes of tropane-based ligands. Opposing stereoselectivity and divergent structural requirements for optimal DAT binding suggest that these tropane-based DAT inhibitors may not access identical binding domains. To further investigate this hypothesis, a series of (S)-2beta-carboalkoxy-3alpha-(bis[4-fluorophenyl]methoxy)tropanes (11a-f, 13-16) and their identically (R)-2beta-substituted 3beta-(3,4-dichlorophenyl)tropanes (3, 5a-d) were prepared and evaluated for binding at the DAT and for inhibition of [(3)H]dopamine uptake in rat brain. These studies showed that most of the identically 2-carboalkoxy-substituted analogues, within the two classes of compounds, bind with high affinity to DAT (K(i) = 5.5-100 nM), albeit with opposite stereochemistry. However, the larger azido- (15) and isothiocyanato- (16) (S)-2beta-carbophenylethoxy-3alpha-(bis[4-fluorophenyl]methoxy)tropanes demonstrated a significant decrease in DAT binding potency (IC(50) = 210 and 537 nM, respectively), suggesting that the DAT does not tolerate 2-position steric bulk in the benztropine class, as it does with the 2-substituted 3-aryltropanes. In addition, binding affinities at the serotonin transporter, norepinephrine transporter, and muscarinic receptors were evaluated and compared for compounds 2, 3, 11a-e, and 13. Together, the binding profiles across these systems demonstrated significant differences between these two classes of tropane-based ligands, which may be exploited toward the discovery of a cocaine-abuse pharmacotherapeutic.

Animals↗

PubMed1995

Comparison of a novel tropane analog of cocaine, 2 beta-propanoyl-3 beta-(4-tolyl) tropane with cocaine HCl in rats: nucleus accumbens extracellular dopamine concentration and motor activity.

2 beta-propanoyl-3 beta-(4-tolyl) tropane (PTT) is a novel tropane that has been shown to be approximately 20 times more potent than cocaine in binding to the 3 beta-[4'-iodophenyl] tropane-2 beta-carboxylic acid methyl ester (RTI-55) site on the dopamine transporter, an effect partially attributable to the methyl constituent at the para position on the phenyl ring. In addition, PTT lacks the ester linkage of cocaine, thus increasing its metabolic stability. This study was undertaken to compare the quantitative and temporal effects of PTT and cocaine on in vivo neurochemical measures and motor behavior. The effects of PTT (0.3, 1.0 and 3.0 mg/kg; i.p.) and cocaine HCl (3.0, 10.0, & 30.0 mg/kg; i.p.) on nucleus accumbens extracellular dopamine concentrations [DA]e were evaluated using in vivo microdialysis. Locomotor activity and stereotypic behaviors were also assessed. PTT and cocaine increased [DA]e and total locomotor activity in a dose-dependent manner with PTT approximately 30 times more potent than cocaine. The relationship between [DA]e and locomotor activity was linear over the test session for cocaine, but not for PTT. In a subsequent experiment, pronounced stereotypic behaviors were evident in rats administered cocaine (10.0 and 30.0 mg/kg) or PTT (3.0 mg/kg). The stereotypy elicited by PTT was longer in duration and greater in intensity than that elicited by the highest dose of cocaine. These results extend previously published data by demonstrating similar in vivo potencies for PTT on nucleus accumbens [DA]e and locomotor activity. However, these data do not support the hypothesis that the time course of increased nucleus accumbens [DA]e and stimulated locomotor activity are related.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1994

Behavioral effects of the novel tropane analog, 2 beta-propanoyl-3 beta-(4-toluyl)-tropane (PTT).

In vitro studies have demonstrated that a novel tropane analog, PTT, in which both of the esters of cocaine have been removed is 20 times more potent than cocaine and more selective than cocaine in binding to dopamine transporters. The present studies compared the ability of PTT and cocaine to stimulate locomotor activity in rats. The intraperitoneal administration of PTT and cocaine to male Fisher-344 rats produced dose-dependent increases in spontaneous locomotor activity and stereotypic behaviors. PTT was 10-20 times more potent than cocaine in this behavioral assay, closely paralleling its potency relative to cocaine in dopamine transporter binding and uptake assays in vitro. PTT, however, elicited a qualitatively different profile of stereotypic behaviors, and PTT had a longer duration of action than cocaine. These results show how changes in kinetics and selectivity of tropanes can affect stimulant-elicited behaviors.

Analysis of Variance↗

PubMed1997

3'-Chloro-3 alpha-(diphenylmethoxy)tropane but not 4'-chloro-3 alpha-(diphenylmethoxy)tropane produces a cocaine-like behavioral profile.

A series of 2'- and 3'-substituted and 3',3"-disubstituted 3 alpha-(diphenylmethoxy)tropane analogs were designed and synthesized as novel probes for the dopamine transporter. All the analogs were evaluated for displacement of [3H]WIN 35,428 binding at the dopamine transporter and for inhibition of [3H]dopamine uptake in rat caudate putamen. Compounds were observed to monophasically displace [3H]WIN 35,428 binding to the dopamine transporter with affinities of 21.6-1836 nM (Ki). Generally, meta-substituted compounds were more potent than benztropine and equipotent to or slightly less potent than their previously reported para-substituted homologs in inhibiting [3H]WIN 35,428 binding. However, these same meta-substituted analogs were typically less potent than the 4'-substituted analogs in inhibiting [3H]dopamine uptake. Ortho-substituted analogs were generally less potent in both binding and inhibition of uptake at the dopamine transporter than either benztropine or other aryl-substituted homologs. The analogs were also tested for binding at norepinephrine and serotonin transporters as well as muscarinic m1 receptors. None of the compounds in the present study bound with high affinity to either the norepinephrine or serotonin transporters, but all bound to muscarinic m1 receptors with high affinity (K1 = 0.41-2.52 nM). Interestingly, 3'-chloro-3 alpha-(diphenylmethoxy)tropane (5c) produced effects like cocaine in animals trained to discriminate 10 mg/kg cocaine from saline, unlike its 4'-Cl homolog and all of the previously evaluated benztropine analogs. Further evaluation of compound 5c and the other benztropine analogs will undoubtedly prove useful in the elucidation of the role of the dopamine transporter in the reinforcing effects of cocaine and the ultimate identification of a cocaine-abuse treatment.

Animals↗

PubMed2000

Characterization of a tropane radioligand, [(3)H]2beta-propanoyl-3beta-(4-tolyl) tropane ([(3)H]PTT), for dopamine transport sites in rat brain.

PTT (2beta-propanoyl-3beta-[4-tolyl] tropane) is a tropane analog relatively selective for dopamine transporters in binding and uptake assays in vitro, with long-acting psychostimulant properties in vivo. To explore its utility in binding to dopamine transporters, [(3)H]PTT was synthesized and assayed for binding in rat striatal membranes and by in vitro autoradiography. In membranes, binding of [(3)H]PTT was saturable to a single class of binding sites with a K(D) value of 3 nM. The pharmacology of [(3)H]PTT binding in striatal membranes was consistent with that of a ligand selective for dopamine transporters, with dopamine-selective compounds being significantly more potent in displacing [(3)H]PTT binding than those for 5-HT or norepinephrine transporters. Although the ability of various transporter inhibitors to displace both [(125)I]RTI-55 and [(3)H]PTT binding correlated significantly with each other, there was a better correlation of inhibitor potencies versus [(3)H]PTT binding and dopamine uptake than versus [(125)I]RTI-55 binding and dopamine uptake. The differences in correlations were most noticeable for compounds relatively selective at the 5-hydroxytryptamine (serotonin) transporter. The autoradiographic distribution of [(3)H]PTT binding in coronal sections was consistent with the known distribution of the dopamine transporter, with high levels of binding evident in caudate nucleus, nucleus accumbens, and olfactory tubercle. Moderate densities of [(3)H]PTT binding were also observed in substantia nigra pars compacta, and ventral tegmental area, as well as in the anterior cingulate cortex and portions of the hypothalamus. In addition, nonspecific binding was less than 5% of total binding. Thus, [(3)H]PTT provides an accurate and convenient marker for the dopamine transporter.

Animals↗

PubMed2000

Biosynthetic studies on the tropane ring system of the tropane alkaloids from Datura stramonium.

Isotopic labelling experiments have been carried out in Datura stramonium root cultures with the following isotopically labelled precursors; [2H3]- [2-13C, 2H3]-, [1-13C, 18O2]-acetates, 2H2O, [2H3-methyl]-methionine, [2-13C]-phenyllactate, [3-2H]-tropine and [2'-13C, 3-2H]-littorine. The study explored the incorporation of isotope into the tropane ring system of littorine 1 and hyoscyamine 2 and revealed that deuterium from acetate is incorporated only into C-6 and C-7, and not into C-2 and C-4 as previously reported. Oxygen-18 was not retained at a detectable level into the C(3)-O bond from [1-13C, 18O2]-acetate. The intramolecular nature of the rearrangement of littorine 1 to hyoscyamine 2 is revealed again by a labelling study using [2'-13C, 3-2H]-littorine, [2-13C]-phenyllactate and [3-2H]-tropine.

Alkaloids↗

PubMed1995

Behavioral and local cerebral metabolic effects of the novel tropane analog, 2 beta-propanoyl-3 beta-(4-tolyl)-tropane.

A novel cocaine analog, 2 beta-propanoyl-3 beta-(4-tolyl)-tropane (PTT), in which both esters have been removed, has been shown to be more potent at and more selective for dopamine transporters than cocaine. The i.v. administration of PTT (0.1-2.0 mg/kg) to rats produced dose-dependent increases in forward locomotor activity and stereotypies at high doses. The 2-[14C]deoxyglucose method was used to measure the effects of PTT (0.1-1.0 mg/kg) on rates of local cerebral glucose utilization. The administration of high doses of PTT (0.5 and 1.0 mg/kg i.v.) resulted in widespread elevations in glucose utilization in portions of the mesocorticolimbic and nigrostriatal systems. Alterations were also noted in hippocampus, locus coeruleus and dorsal raphe. In contrast, a low dose of PTT (0.1 mg/kg) decreased cerebral metabolic activity in the nucleus accumbens and olfactory tubercle, with few effects in other regions. Decreased metabolic rates at low doses have not been observed with other stimulants and, therefore, represent a unique effect of this analog. The administration of the active enantiomer of PTT (0.075 mg/kg), approximately comparable to the 0.1 mg/kg of the racemic mixture, produced patterns of behavior and cerebral metabolic activity similar to the 0.1 mg/kg dose. The effects of PTT, then, are specific to its active enantiomer rather than the inactive form. The present data demonstrate that PTT acts as a stimulant in vivo, paralleling its effects in vitro, but its behavioral and cerebral metabolic effects are qualitatively different from those of cocaine. This is consistent with the selectivity and pharmacokinetic differences between PTT and cocaine.

Animals↗

PubMed1998

Long-acting blockade of biogenic amine transporters in rat brain by administration of the potent novel tropane 2beta-propanoyl-3beta-(2-Naphthyl)-tropane.

2beta-Propanoyl-3beta-(2-naphthyl)-tropane (WF-23) is a potent cocaine analog with activity at dopamine and serotonin transporters. The purpose of these experiments was to characterize the time course of effects of acute administration of WF-23 on spontaneous locomotion and biogenic amine transporters. Rats received injections i.p. with WF-23 (1 mg/kg), cocaine (30 mg/kg) or vehicle and locomotor activity was measured at various times postinjection. Animals were killed immediately after behavioral activity. Locomotor activity was significantly increased by WF-23 administration, reaching maximum at 4 hr and persisting for 24 hr. Cocaine-elicited elevations in locomotor activity occurred only at the earliest times. WF-23 decreased DA transporter binding in striatal membranes ([125I]RTI-55 binding), with >50% loss in binding for up to 49 hr postinjection. WF-23 increased the Kd of the high affinity site, with no effect on Bmax. Cocaine depressed binding (20%) only at the earliest times. WF-23 decreased levels of [3H]WIN 35,428 binding sites up to 95% of control in both dorsal and ventral striatum with a similar time-course when assessed autoradiographically. WF-23 also reduced [3H]citalopram binding to serotonin transporter sites throughout the brain. The slow onset and very long duration of action of WF-23, taken together with its actions at dopamine and serotonin transporters, suggest a potential role for treatment of disorders characterized by their involvement of these neural systems.

Animals↗

PubMed1993

Binding of the cocaine analog 2 beta-carbomethoxy-3 beta-(4-[125I]iodophenyl)tropane to serotonin and dopamine transporters: different ionic requirements for substrate and 2 beta-carbomethoxy-3 beta-(4-[125I]iodophenyl)tropane binding.

The iodinated cocaine analog 2 beta-carbomethoxy-3 beta-(4- [125I]iodophenyl)tropane (beta-[125I]CIT) binds with high affinity to the platelet plasma membrane serotonin transporter, as previously reported for dopamine transporters from rat brain [Eur. J. Pharmacol. 194:133-134 (1991)]. Unlabeled beta-CIT also inhibits serotonin transport by platelet membrane vesicles. In both rat striatal membranes and platelet plasma membranes, beta-[125I]CIT binding was found to be pH dependent, with a pKa of 6.4-6.9, and did not require the presence of Cl-. Na+ dramatically stimulated beta-[125I]CIT binding to both serotonin and dopamine transporters, although a small fraction of beta-[125I]CIT binding to the serotonin transporter was observed in the absence of Na+. The substrates serotonin and dopamine competed with beta-[125I]CIT for binding to their respective transporters. However, substrate affinity was enhanced by Cl-, whereas beta-[125I]CIT binding affinity was not. [3H]Imipramine binding to the platelet serotonin transporter and [3H]GBR-12935 binding to the dopamine transporter were not inhibited by decreasing the pH from 8 to 6.5. Likewise, the ability of serotonin to compete with [3H]imipramine binding and that of dopamine to inhibit [3H]GBR-12935 binding were equal at pH 6.5 or 8. Thus, beta-[125I]CIT binding to biogenic amine transporters is distinct from serotonin or dopamine binding by virtue of its inhibition by H+ and its insensitivity to Cl-.

Animals↗

PubMed1962