ABSTRACT
BACKGROUND: The proliferation of novel psychoactive substances (NPS) in the drug market raises concerns about uncertainty on their pharmacological profile and the health hazard linked to their use. Within the category of synthetic stimulant NPS, the phenethylamine 2-Cl-4,5-methylenedioxymethamphetamine (2-Cl-4,5-MDMA) has been linked to severe intoxication requiring hospitalization. Thereby, the characterization of its pharmacological profile is urgently warranted. METHODS: By in vivo brain microdialysis in adolescent and adult male rats we investigated the effects of 2-Cl-4,5-MDMA on dopamine (DA) and serotonin (5-HT) neurotransmission in two brain areas critical for the motivational and rewarding properties of drugs, the nucleus accumbens (NAc) shell and the medial prefrontal cortex (mPFC). Moreover, we evaluated the locomotor and stereotyped activity induced by 2-Cl-4,5-MDMA and the emission of 50-kHz ultrasonic vocalizations (USVs) to characterize its affective properties. RESULTS: 2-Cl-4,5-MDMA increased dialysate DA and 5-HT in a dose-, brain area-, and age-dependent manner. Notably, 2-Cl-4,5-MDMA more markedly increased dialysate DA in the NAc shell and mPFC of adult than adolescent rats, while the opposite was observed on dialysate 5-HT in the NAc shell, with adolescent rats being more responsive. Furthermore, 2-Cl-4,5-MDMA stimulated locomotion and stereotyped activity in both adolescent and adult rats, although to a greater extent in adolescents. Finally, 2-Cl-4,5-MDMA did not stimulate the emission of 50-kHz USVs. CONCLUSIONS: This is the first pharmacological characterization of 2-Cl-4,5-MDMA demonstrating that its neurochemical and behavioral effects may differ between adolescence and adulthood. These preclinical data could help understanding the central effects of 2-Cl-4,5-MDMA by increasing awareness on possible health damage in users.
Subject(s)
Dopamine , Nucleus Accumbens , Prefrontal Cortex , Serotonin , Animals , Male , Nucleus Accumbens/drug effects , Nucleus Accumbens/metabolism , Dopamine/metabolism , Serotonin/metabolism , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Rats , Locomotion/drug effects , Microdialysis , Age Factors , Behavior, Animal/drug effects , Stereotyped Behavior/drug effects , Vocalization, Animal/drug effects , N-Methyl-3,4-methylenedioxyamphetamine/pharmacology , N-Methyl-3,4-methylenedioxyamphetamine/administration & dosage , Rats, Wistar , Hallucinogens/pharmacologyABSTRACT
The development of novel µ-opioid receptor (MOR) antagonists is one of the main objectives of drug discovery and development. Based on a simplified version of the morphinan scaffold, 3-[3-(phenalkylamino)cyclohexyl]phenol analogs were designed, synthesized, and evaluated for their MOR antagonist activity in vitro and in silico. At the highest concentrations, the compounds decreased by 52% to 75% DAMGO-induced GTPγS stimulation, suggesting that they acted as antagonists. Moreover, Extra-Precision Glide and Generalized-Born Surface Area experiments provided useful information on the nature of the ligand-receptor interactions, indicating a peculiar combination of C-1 stereochemistry and N-substitutions as feasibly essential for MOR-ligand complex stability. Interestingly, compound 9 showed the best experimental binding affinity, the highest antagonist activity, and the finest MOR-ligand complex stability. In silico experiments also revealed that the most promising stereoisomer (1R, 3R, 5S) 9 retained 1,3-cis configuration with phenol ring equatorial oriented. Further studies are needed to better characterize the pharmacodynamics and pharmacokinetic properties of these compounds.
Subject(s)
Naltrexone , Narcotic Antagonists , Naltrexone/pharmacology , Narcotic Antagonists/pharmacology , Narcotic Antagonists/chemistry , Ligands , Phenols/pharmacology , Structure-Activity Relationship , Receptors, Opioid, mu/chemistry , Receptors, Opioid, mu/metabolismABSTRACT
The isolation of the antitumor antibiotic anthramycin in the 1960s prompted extensive research into pyrrolo[1,4]benzodiazepines (PBD) as potential therapeutics for the treatment of cancers. Since then, nearly 60 PBD natural products have been isolated and evaluated with regard to their biological activity. Synthetic studies and total syntheses have enabled access to PBD analogues, culminating in the development of highly potent anticancer agents. This review provides a summary of the occurrence and biological activity of PBD natural products and covers the strategies employed for their total syntheses.
