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At least 19 recordsLinked to original sources
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↗
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↗
PubMed1984

[Effect of tropane on the cholinoreceptors of the cerebral cortex].

Spontaneous electric activity of single neurons of the sensorimotor cortex was recorded extracellularly in experiments on unanesthetized rabbits. During microiontophoretic application of tropane and acetylcholine to the neurons, the response to both the agents was the same. The cells excitable by acetylcholine are also excitable by tropane, while those inhibited by acetylcholine are also inhibited by tropane. The cells that do not respond to acetylcholine are also irresponsive to tropane. The excitatory response pattern to tropane is similar to that of acetylcholine. Under the same conditions of microiontophoretic application, tropane causes less excitation as compared with acetylcholine. Tropane preliminarily applied to the neuron reduces the excitatory effect of acetylcholine. The possible role of agonist-antagonist relations between tropane and acetylcholine in the mechanism of the pharmacological effects of tropane and its derivatives is discussed.

Acetylcholine↗
PubMed1995

Cocaine and 3 beta-(4'-substituted phenyl)tropane-2 beta-carboxylic acid ester and amide analogues. New high-affinity and selective compounds for the dopamine transporter.

Several 2 beta-carboxylic acid ester and amide analogues of cocaine and of 3 beta-(4'-substituted phenyl)tropane-2 beta-carboxylic acid were prepared. The binding affinities of these compounds, and of some previously prepared analogues, at the dopamine (DA), norepinephrine (NE), and serotonin (5-HT) transporters were determined. The phenyl esters of 3 beta-(4'-methylphenyl)- and 3 beta-(4'-chlorophenyl)tropane-2 beta-carboxylic acid are highly potent and highly selective for the DA transporter. The isopropyl esters of 3 beta-(4'-chlorophenyl)- and 3 beta-(4'-iodophenyl)tropane-2 beta-carboxylic acid also possess high DA affinity and show significant DA transporter selectivity. Similarly, the phenyl and isopropyl ester analogues of cocaine are much more selective for the DA transporter than cocaine. Tertiary amide analogues of cocaine and of 3 beta-(4'-substituted phenyl)tropane-2 beta-carboxylic acids are more potent inhibitors of radioligand binding at the DA transporter than the primary and secondary amide analogues. In particular, 3 beta-(4'-chlorophenyl)tropane-2 beta-N-morpholinocarboxamide as well as the 3 beta-(4'-chlorophenyl)- and 3 beta-(4'-iodophenyl)tropane-2 beta-N- pyrrolidinocarboxamides possess high affinity and selectivity for the DA transporter. The N,N-dimethylamide cocaine analogue is the most selective cocaine amide derivative for the DA transporter. High correlation between the inhibition of radioligand binding and inhibition of uptake at the DA, NE, and 5-HT transporter was found for a selected group of analogues. Within this group, one compound, the isopropyl ester of 3 beta-(4'-iodophenyl)-tropane-2 beta-carboxylic acid, was found to be more potent in the inhibition of radioligand binding than in the inhibition of DA uptake. Taken together with its high potency and selectivity at the DA transporter, this suggests that this compound may be a lead in the development of a cocaine antagonist.

Amides↗
PubMedDate not supplied

[Mechanism of the central effects of tropane].

The effect of tropan on exocellular-recorded electrical activity of brain sensorimotor cortical and ventrolateral thalamic neurons was studied in acute experiments on rabbits. Tropan was injected intravenously in a dose of 1-5 mg/kg and applied microiontophoretically to individual neurons. With both routes of administration tropan increased the frequency of spontaneous activity of the majority of cortical and thalamic neurons in the dose-dependent form. The inhibitory action of the microiontophoretically applied catecholamines noradrenaline and dopamine on the activity of brain cortical neurons does not change under the effect of tropan. The stimulatory effect of catecholamines on ventrolateral thalamic neurons is potentiated by tropan. It is suggested that excitation of cortical and subcortical neurons, as well as potentiation of stimulatory catecholaminergic effects in the subcortex underlie the central stimulant effect of tropan.

Action Potentials↗
PubMed1995

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.

Animals↗
PubMed1992

Opioid properties of some derivatives of pethidine based on tropane.

The preparation of some tropane analogues of pethidine and its reversed ester, chiefly with preferred 3 alpha-m-hydroxyphenyl chair conformations, is described. The former were secured from tropan-3-one in a sequence of reactions involving cyanide attack, hydrolysis, Grignard attack and then rearrangements. The reversed ester was obtained by treating tropan-3-one with lithium phenyl, followed by acylation. Configurational and conformational assignments follow from NMR analysis. The antinociceptive potencies of these compounds in mice are reported, and discussed in relation to non-phenolic congeners and the 4-arylpiperidine moiety of morphine.

Analgesics↗
PubMed1991

[Study on separation and determination of four tropane alkaloids in crude drugs by micellar HPLC].

A new method for separation and determination of four important tropane alkaloids (hyoscyamine, scopolamine, anisodamine and anisodine) in crude drugs by micellar HPLC was developed. The mobile phase was optimized with the modified simplex method (MSM). The chromatographic response function (CRF) was used as the criterion of optimization and three dimension simplex was used in this course. After eight tests, the given accuracy was achieved. In the optimized system the four tropane alkaloids are separated not only from each other but also from the interfering components in the crude drugs. The CMC of SDS in mobile phase was determined to be 5 mmol/L by circle method. The experimental evidences show that the optimized system is micellar chromatography. This method is simple, sensitive and accurate. The extraction solution can be injected directly without the need of a general purification procedure. Several plant materials containing tropane alkaloids were determined. The results and chromatograms are reported in this paper.

Atropine↗
PubMed1985

[Central cholinolytic effect of tropane derivatives: structure-activity relationship].

The effect of two tropane derivatives on the electric neuronal activity in sensorimotor cortex was studied in rabbits using microiontophoretic method. Unlike atropine they lack aryl and hydroxyl, but possess morpholine and piperazine. The effects of both drugs were opposite to those of acetylcholine. Simultaneous application of tropane derivatives and acetylcholine to one neuron decreased both excitatory and inhibitory neuronal responses to acetylcholine. It is concluded that aryl and hydroxyl are not necessary for tropane derivatives to reveal their central cholinolytic activity.

Action Potentials↗
PubMed2026

A Comprehensive Review on the Biosynthesis of Tropane Alkaloids.

Tropane alkaloids (TA) constitute a class of plant specialized metabolites with important pharmaceutical applications, including the anticholinergic agents hyoscyamine and scopolamine and the local anesthetic cocaine. Over the past decade, advances in genomics, structural biology, and synthetic biology have substantially revised our understanding of TA biosynthesis, leading to the identification of numerous key biosynthetic enzymes and evolutionary mechanisms. This review comprehensively summarizes current knowledge of TA biosynthesis from precursor formation to structurally diverse end products. We describe the pathway from putrescine to tropinone, the stereoselective metabolic branching mediated by Tropinone Reductases, and the downstream biosynthesis of medicinal tropane alkaloids, calystegines, and cocaine. Particular emphasis is placed on recent discoveries concerning catalytic mechanisms, structural determinants of substrate specificity, metabolic compartmentalization, and the convergent evolution of TA biosynthesis in Solanaceae and Erythroxylaceae. We further integrate advances in genomics, evolutionary biology, and metabolic engineering to highlight emerging strategies for microbial production and pathway redesign. By providing a comprehensive synthesis of recent progress and critical perspectives on unresolved questions, this review offers an updated framework for understanding TA biosynthesis and supports future research in plant specialized metabolism, synthetic biology, and natural product engineering.

Tropanes↗
PubMed1995

Tropane alkaloids and toxicity of Convolvulus arvensis.

Horses in a few, localized northern Colorado pastures exhibited weight loss and colic. At post mortem, intestinal fibrosis and vascular sclerosis of the small intestine was identified. The pastures where the affected horses grazed were overrun by field bindweed (Convolvulus arvensis). Bindweed from the pasture was found to contain the tropane alkaloids tropine, pseudotropine, and tropinone and the pyrrolidine alkaloids cuscohygrine and hygrine. Laboratory mice readily ate C. arvensis and exhibited a variety of abnormal clinical signs depending on the amount eaten. Similar alkaloids have been found in other Convolvulus species and cuscohygrine and calystegines (polyhydroxytropanes) have been previously reported from C. arvensis roots. This is the first report of simple tropane alkaloids in C. arvensis, a world wide problem weed. Pseudotropine, the major alkaloid, is known to affect motility and might represent a causative agent for the observed cases of equine intestinal fibrosis.

Animals↗
PubMed1991

Synthesis and receptor binding of N-substituted tropane derivatives. High-affinity ligands for the cocaine receptor.

The synthesis and pharmacological characterization of a series of N-substituted 3-(4-fluorophenyl)tropane derivatives is reported. The compounds displayed binding characteristics that paralleled those of cocaine, and several had substantially higher affinity at cocaine recognition sites. Conjugate addition of 4-fluorophenyl magnesium bromide to anhydroecgonine methyl ester gave 2 beta-(carbomethoxy)-3 beta-(4-fluorophenyl)tropane (4a, designated CFT, also known as WIN 35,428) after flash chromatography. N demethylation of 4a was effected by Zn/HOAc reduction of the corresponding 2,2,2-trichloroethyl carbamate to give 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)nortropane (5), which was alkylated with allyl bromide to afford the N-allyl analogue, 6. The N-propyl analogue, 7, was prepared by catalytic reduction (Pd/C) of 6. The most potent analogue, 4a, was tritiated at a specific activity of 81.3 Ci/mmol. [3H]4a bound rapidly and reversibly to caudate putamen membranes; the two-component binding curve typical of cocaine analogues was observed. Equilibrium was achieved within 2 h and was stable for at least 4 h. High- and low-affinity Kd values observed for [3H]4a (4.7 and 60 nM, respectively) were more than 4 times lower than those for [3H]cocaine, and the density of binding sites (Bmax = 50 pmol/g, high, and 290 pmol/g, low) for the two drugs were comparable. Nonspecific binding of [3H]4a was 5-10% of total binding.

Animals↗
PubMed1990

Recent developments in the biosynthesis of the tropane alkaloids.

Recent work on the biosynthesis of the tropane moiety of cocaine, hyoscamine, scopolamine, and related alkaloids is reviewed. Revision of the generally accepted biosynthetic pathway to these alkaloids is now proposed in the light of new discoveries. New information on the biosynthesis of some of the acid moieties (benzoic, tiglic and tropic acid) of the tropane ester alkaloids is also discussed.

Acids↗
PubMed1989

Production of tropane alkaloids by cultured cells of a Duboisia hybrid.

The production of scopolamine-rich calli was investigated by the quantification of tropane alkaloids in a gas chromatograph equipped with a flame thermoionic detector (FTD). Stem and leaf segments from a selected strain, M-II-8-6, a hybrid between Duboisia myoporoides R. Br. and D. leichhardtii F. Muell, were used for this experiment. Stem-derived callus subcultured for over one year in the dark on Murashige-Skoog (MS) medium containing 0.1 mg/l indole-3-acetic acid (IAA) produced hyoscyamine ane scopolamine with a yield of 0.006 and 0.005% dry weight, respectively. Leaves of shoot cultures did not show any detectable levels of alkaloids. However, the leaf callus subcultured for over one year in the dark on MS medium containing 0.1 mg/l IAA produced hyoscyamine and scopolamine with a yield of 0.007 and 0.009% dry weight, respectively. These results indicate that the ability to synthesize tropane alkaloids in stem- and leaf-derived calli can be maintained on MS medium containing IAA.

Cells, Cultured↗
PubMed1987

[Synthesis and pharmacology of N-stereoisomers of quaternary tropane compounds].

The synthesis of (8r)-8-(4-biphenylmethyl)-atropinium bromide (3) as N-isomeric form of xenytropium bromide, (8s)-8-(4-biphenylmethyl)-atropinium bromide (2), is reported. It was revealed, that the equatorial alkylation predominates in quaternization of tertiary tropane compounds. Furthermore, the preparation of other N-isomeric pairs of quaternary tropane derivatives in pure form is described. Xenytropium bromide is more active--16 times on the parasympathic endplate and 8 times on the ganglion--than its N-isomer.

Atropine Derivatives↗
PubMedDate not supplied

[Tropane ligands of different types of opiate receptors].

Interaction of tropane derivatives (motropin, atropine, cocaine) with opiates (morphine) and opioids (an enkephalin amide analog) was studied according to varying tests: pain sensitivity, impulse summation in the central nervous system, respiration. It appeared that motropin is a morphine antagonist and enkephalin amide analog from the standpoint of effect on analgetic action and impulse summation, but is not their antagonist as regards the effect on respiration. Atropine is a weak morphine antagonist in terms of the effect on analgesia, impulse summation and respiration as well. Cocaine is a morphine synergist as regards all the tests indicated. Therefore, the effect of tropane derivatives on pain sensitivity, impulse summation and respiration is mediated via different opiate receptors, which does not exclude the involvement of other neurochemical mechanisms in their action.

Animals↗