Mixed Cocaine Agonist/Antagonist Properties of (+)-Methyl 4β-(4-Chlorophenyl)-1-methylpiperidine-3α-carboxylate, a Piperidine-Based Analog of Cocaine

@article{Kozikowski2003MixedCA,
  title={Mixed Cocaine Agonist/Antagonist Properties of (+)-Methyl 4$\beta$-(4-Chlorophenyl)-1-methylpiperidine-3$\alpha$-carboxylate, a Piperidine-Based Analog of Cocaine},
  author={Alan P. Kozikowski and Kenneth M. Johnson and Olivier Deschaux and Bidhan C. Bandyopadhyay and Gian Luca Araldi and Gilberto N. Carmona and Patrik Munzar and Miles P. Smith and Robert L. Balster and Patrick M Beardsley and Srihari R. Tella},
  journal={Journal of Pharmacology and Experimental Therapeutics},
  year={2003},
  volume={305},
  pages={143 - 150}
}
The present study investigated the pharmacological properties of a piperidine-based novel cocaine analog, namely, (+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylic acid [(+)-CPCA]. Like cocaine, (+)-CPCA inhibited rat synaptosomal dopamine and norepinephrine uptake with high affinity, but was 33-fold less potent than cocaine in inhibiting serotonin uptake. Like cocaine, (+)-CPCA is a locomotor stimulant, although it was less potent and efficacious than cocaine. Importantly… 

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References

SHOWING 1-10 OF 51 REFERENCES
Discovery of a novel dopamine transporter inhibitor, 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone, as a potential cocaine antagonist through 3D-database pharmacophore searching. Molecular modeling, structure-activity relationships, and behavioral pharmacological studies.
TLDR
Data suggest that 6 represents a promising lead for further evaluations as potential therapy for the treatment of cocaine abuse, and finds that hydrophobicity and conformational preference are two additional important parameters that determine affinity at the DAT site.
Effects of cocaine and related drugs in nonhuman primates. II. Stimulant effects on schedule-controlled behavior.
TLDR
The results combined with previous studies demonstrate a close correspondence between the potencies of 15 different drugs for producing cocaine-like behavioral effects and for displacing specifically bound [3H]cocaine in caudate-putamen.
Reinforcing Strength of a Novel Dopamine Transporter Ligand: Pharmacodynamic and Pharmacokinetic Mechanisms
TLDR
The results suggest that (+)-CPCA is a weaker positive reinforcer than cocaine because it has a slower onset of action over the first few minutes after i.v. injection.
Discriminative stimulus properties of cocaine: enhancement by monoamine reuptake blockers.
  • M. Kleven, W. Koek
  • Biology, Psychology
    The Journal of pharmacology and experimental therapeutics
  • 1998
TLDR
Analysis of the relationship between behavioral and in vitro biochemical potencies indicated that inhibition of DA and 5-HT transport is responsible for the cocaine-enhancing effects of the monoamine reuptake blockers, and suggested that NE interactions may be relatively less important in the rat.
Serotonin-facilitated dopamine release in vivo: pharmacological characterization.
TLDR
The receptor specificity of serotonin (5-HT) agonist-induced facilitation of dopamine (DA) release was assessed by using in vivo microdialysis and coperfusion of antagonists with agonists indicated involvement of 5-HT1 and 5- HT3 receptors and a lack of involvement of 6-methyl-5H-thiazolo-1-pyrimidin-5-one receptors.
Monoamine reuptake inhibitors enhance the discriminative state induced by cocaine in the rat
TLDR
The finding that GBR 12909 mimics the cocaine cue corroborates the hypothesis that the stimulus properties of cocaine are mediated predominantly by DA systems and suggests that monoamine reuptake inhibitors could also amplify the subjective effects of cocaine in humans.
Evaluation of the cocaine-like discriminative stimulus effects and reinforcing effects of modafinil
TLDR
Results show that modafinil has some cocaine-like discriminative stimulus effects and, like other abused stimulants, can serve as a reinforcer at high doses.
Effects of cocaine and related drugs in nonhuman primates. I. [3H]cocaine binding sites in caudate-putamen.
TLDR
Binding of [3H]cocaine was NaCl-dependent, with specific binding reduced by 72% when NaCl (100 mM) was omitted from the incubation medium, and dopamine was considerably more potent than either norepinephrine or serotonin.
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4
5
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