A two-dose regimen of Qβ virus-like particle-based vaccines elicit protective antibodies against heroin and fentanyl.

Opioid overdoses and the growing rate of opioid use disorder (OUD) are major public health concerns, particularly in the United States. Current treatment approaches for OUD have failed to slow the growth of the opioid crisis. Opioid vaccines have shown pre-clinical success in targeting multiple different opioid drugs.

Assessment of the antinociceptive, respiratory-depressant, and reinforcing effects of the low pK fluorinated fentanyl analogs, FF3 and NFEPP.

Rationale: Recent studies report that fentanyl analogs with relatively low pK values produce antinociception in rodents without other mu opioid-typical side effects due to the restriction of their activity to injured tissue with relatively low pH values. However, it is unclear if and to what degree these compounds may produce mu opioid-typical side effects (respiratory depression, reinforcing effects) at doses higher than those required to produce antinociception.

Objectives: The present study compared the inflammatory antinociceptive, respiratory-depressant, and reinforcing effects of fentanyl and two analogs of intermediate (FF3) and low (NFEPP) pK values in terms of potency and efficacy in male and female Sprague-Dawley rats.

Identification of a Potent Human Trace Amine-Associated Receptor 1 Antagonist.

Human trace amine-associated receptor subtype 1 (hTAAR1) is a G protein-coupled receptor that has therapeutic potential for multiple diseases, including schizophrenia, drug addiction, and Parkinson's disease (PD). Although several potent agonists have been identified and have shown positive results in various clinical trials for schizophrenia, the discovery of potent hTAAR1 antagonists remains elusive. Herein, we report the results of structure-activity relationship studies that have led to the discovery of a potent hTAAR1 antagonist (RTI-7470-44, ).

Conformationally constrained analogues of N-(piperidinyl)-5-(4-chlorophenyl)-1-(2,4- dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716): design, synthesis, computational analysis, and biological evaluations.

Structure-activity relationships (SARs) of 1 (SR141716) have been extensively documented, however, the conformational properties of this class have received less attention. In an attempt to better understand ligand conformations optimal for receptor recognition, we have designed and synthesized a number of derivatives of 1, including a four-carbon-bridged molecule (11), to constrain rotation of the diaryl rings. Computational analysis of 11 indicates approximately 20 kcal/mol energy barrier for rotation of the two aryl rings.

Conformational characteristics of the interaction of SR141716A with the CB1 cannabinoid receptor as determined through the use of conformationally constrained analogs.

Interest in cannabinoid pharmacology increased dramatically upon the identification of the first cannabinoid receptor (CB1) in 1998 and continues to expand as additional endocannabinoids and cannabinoid receptors are discovered. Using CB1 receptor (CB1R) systems, medicinal chemistry programs began screening libraries searching for cannabinoid ligands, ultimately leading to the discovery of the first potent cannabinoid receptor antagonist, SR141716A (Rimonabant). Its demonstrated efficacy in treating obesity and facilitating smoking cessation, among other impressive pharmacological activities, has furthered the interest in cannabinoid receptor antagonists as therapeutics, such that the number of patents and publications covering this class of compounds continues to grow at an impressive rate.