Characterization of the Neurochemical and Behavioral Effects of the Phenethylamine 2-Cl-4,5-MDMA in Adolescent and Adult Male Rats.

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.

3-[3-(Phenalkylamino)cyclohexyl]phenols: Synthesis, biological activity, and in silico investigation of a naltrexone-derived novel class of MOR-antagonists.

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.

Discovery, synthesis, and structure-activity relationships of 2-aminoquinazoline derivatives as a novel class of metabotropic glutamate receptor 5 negative allosteric modulators.

A virtual screening approach using various in silico methodologies led to the discovery of 2-(m-tolylamino)-7,8-dihydroquinazolin-5(6H)-one (1) as a moderately active negative allosteric modulator (NAM) of the metabotropic glutamate receptor subtype 5 (mGluR5) showing high selectivity against the subtype mGluR1. Modifications of the parent compound by rational design yielded a series of highly potent derivatives which will serve as valuable starting points for further hit-to-lead optimization efforts toward a suitable drug candidate for the treatment of L-DOPA induced dyskinesia.

Positive and negative modulation of group I metabotropic glutamate receptors.

A discriminating pharmacophore model for noncompetitive metabotropic glutamate receptor antagonists of subtype 1 (mGluR1) was developed that facilitated the discovery of moderately active mGluR1 antagonists. One scaffold was selected for the design of several focused libraries where different substitution patterns were introduced. This approach facilitated the discovery of potent mGluR1 antagonists, as well as positive and negative mGluR5 modulators, because both receptor subtypes share similar binding pockets. For mGluR1 antagonists, a homology model of the mGlu1 receptor was established, and a putative binding mode within the receptor's transmembrane domain was visualized.