Kinetics of human cannabinoid 1 (CB1) receptor antagonists: Structure-kinetics relationships (SKR) and implications for insurmountable antagonism.

While equilibrium binding affinities and in vitro functional antagonism of CB1 receptor antagonists have been studied in detail, little is known on the kinetics of their receptor interaction. In this study, we therefore conducted kinetic assays for nine 1-(4,5-diarylthiophene-2-carbonyl)-4-phenylpiperidine-4-carboxamide derivatives and included the CB1 antagonist rimonabant as a comparison. For this we newly developed a dual-point competition association assay with [H]CP55940 as the radioligand.

Loxapine add-on for adolescents and adults with autism spectrum disorders and irritability.

Objectives: Our clinical experience with low dose loxapine (5-15 mg/day) suggests promising efficacy and safety for irritability in autism spectrum disorders (ASD). We studied low dose loxapine prospectively in adolescents and adults with ASD and irritability. Additionally, we measured loxapine and metabolite concentrations, and brain-derived neurotrophic factor (BDNF) as a biomarker of neuromodulation.

Synthesis and preliminary evaluation of a new fluorine-18 labelled triazine derivative for PET imaging of cannabinoid CB2 receptor.

Cannabinoid CB2 PET tracers are considered as a promising alternative to PBR/TSPO tracers for the in-vivo imaging of neuroinflammation. We describe here the synthesis and characterization of compound 3, a new potent and brain penetrating CB2 ligand based on an original triazine template. The PET tracer [(18)F]-dideutero-3 was prepared in a three steps radiosynthesis, and demonstrated significant uptake in rhesus macaque and baboon brain with a maximum SUV of about 0.

Mastering tricyclic ring systems for desirable functional cannabinoid activity.

There is growing interest in using cannabinoid receptor 2 (CB2) agonists for the treatment of neuropathic pain and other indications. In continuation of our ongoing program aiming for the development of new small molecule cannabinoid ligands, we have synthesized a novel series of carbazole and γ-carboline derivatives. The affinities of the newly synthesized compounds were determined by a competitive radioligand displacement assay for human CB2 cannabinoid receptor and rat CB1 cannabinoid receptor.

Rational design of a novel peripherally-restricted, orally active CB(1) cannabinoid antagonist containing a 2,3-diarylpyrrole motif.

A new series of 2,3-diarylpyrroles have been prepared and evaluated as CB(1) antagonists. Modulation of the topological polar surface area allowed the identification of high affinity peripherally-restricted CB(1) antagonists. Compound 11, obtained after further optimization of the metabolic profile displayed very low brain penetration, yet was able to reverse CP55940-induced gastrointestinal transit inhibition following oral administration.

Overnight versus progressive conversion of multiple daily-dose divalproex to once-daily divalproex extended release: which strategy is better tolerated by adults with intellectual disabilities?

Divalproex (DVP) delayed release and DVP extended release (DVP ER) are approved by the Food and Drug Administration for bipolar disorder, epilepsy, and migraine prophylaxis. Divalproex ER is given once daily, improving compliance and reducing adverse events. Overnight switch to DVP ER is advised in the package insert but could produce more adverse events in this susceptible population.

[Pharmacology of cannabinoid receptors].

The endocannabinoid (EC) system is a physiological system with an important regulatory role in numerous biological functions, both centrally and peripherally. In certain conditions it can become hyperactive and induce a variety of disorders. The system has two receptor types, designated CB1 and CB2 (present respectively in the CNS and the periphery), as well as endogenous ligands (AEA and 2-AG) and equipment for transporting, synthesizing and degrading them.

SR147778 [5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide], a new potent and selective antagonist of the CB1 cannabinoid receptor: biochemical and pharmacological characterization.

Based on binding, functional, and pharmacological data, this study introduces SR147778 [5-(4-bromophenyl)-1-(2,4-dichloro-phenyl)-4-ethyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide] as a highly potent, selective, and orally active antagonist for the CB1 receptor. This compound displays nanomolar affinity (Ki = 0.56 and 3.

Carbon-11 labeled radioligands for imaging brain cannabinoid receptors.

Two radioligands, [(11)C] SR149080 and its morpholino analog [(11)C] SR149568, were synthesized by reaction of the respective phenolic precursors with [(11)C] methyl iodide. Both radioligands had appropriate regional brain distribution for cannabinoid receptors in mice with peak target to non-target ratios of 2.2 for [(11)C] SR149080 and 1.