Synthesis and functional evaluation of proteinogenic amino acid-derived synthetic cannabinoid receptor agonists related to MPP-5F-PICA, MMB-5F-PICA, and MDMB-5F-PICA.

Synthetic cannabinoid receptor agonists (SCRAs) comprise the second largest class of new psychoactive substances (NPS), and typically α-amino acid moieties are incorporated as part of their design. Limited investigation has been performed into elucidating structure-activity relationships around commonly used α-amino acid-derived head groups, mainly with valine and tert-leucine-derived compounds previously described. As such, proactive synthesis, characterisation and pharmacological evaluation were performed to explore structure-activity relationships of 15 α-amino acid derivatives, with both the natural isomers and their enantiomers at CB1 and CB2 investigated using a fluorescence-based membrane potential assay. This library was based around the detected SCRAs MPP-5F-PICA, MMB-5F-PICA, and MDMB-5F-PICA, with the latter showing significant receptor activation at CB1 (pEC50 = 8.34 ± 0.05 M; E max = 108 ± 3%) and CB2 (pEC50 = 8.13 ± 0.07 M; E max = 99 ± 2%). Most valine and leucine derivatives were potent and efficacious SCRAs, while smaller derivatives generally showed reduced activity at CB1 and CB2, and larger derivatives also showed reduced activity. SAR trends observed were rationalised via in silico induced fit docking. Overall, while natural enantiomers showed equipotent or greater activity than the unnatural isomers in most cases, this was not universal. As such, a number of these compounds should be monitored as emerging NPS, and various substituents described herein.

Structure-Activity Relationships, Deuteration, and Fluorination of Synthetic Cannabinoid Receptor Agonists Related to AKB48, 5F-AKB-48, and AFUBIATA.

Synthetic cannabinoid receptor agonists (SCRAs) are a growing class of new psychoactive substances (NPS) commonly derived from an N-alkylated indole, indazole, or 7-azaindole scaffold. Diversification of this core (at the 3-position) with amide-linked pendant amino acid groups and modular N-alkylation (of the indole/indazole/7-azaindole core) ensures that novel SCRAs continue to enter the illicit drug market rapidly. In response to the large number of SCRAs that have been detected, pharmacological evaluation of this NPS class has become increasingly common. Adamantane-derived SCRAs have consistently appeared throughout the market since 2011, and as such, a systematic set of these derivatives was synthesized and pharmacologically evaluated. Deuterated and fluorinated adamantane derivatives were prepared to evaluate typical hydrogen bioisosteres, as well as evaluation of the newly detected AFUBIATA.

P2X receptor antagonists and their potential as therapeutics: a patent review (2010-2021).

INTRODUCTION: Purinergic receptors play a critical role in neurotransmission, and modulation of complex physiological functions and thus have implications in numerous disease states. The past decade has seen substantial progress in the design of novel chemical compounds that act on the P2X class of receptors and warrants an updated review of this field. AREAS COVERED: This review provides a summary of the patent literature describing the discovery and clinical uses of P2X receptor antagonists published between 2010 and September 2021. The reader will gain information on structural claims, representative structures, and biological data of recently reported P2X antagonists. EXPERT OPINION: Despite continual advancement in both crystallography and chemical biology strengthening our understanding of purinergic signalling, there remains an absence of clinically approved chemotypes. A testament to both the therapeutic potential and academic perseverance in purinergic research is the multitude of research initiatives that maintain active P2X receptor programs that have spanned decades. Very recently, the FDA declined Merck Pharmaceuticals application for Gefapixant, a P2X3 selective inhibitor as a treatment for chronic cough, requesting additional data. This unfortunate setback will ultimately be insignificant considering the long history of P2X investigation and the preclinical and clinical development that will undoubtedly occur over the next decade.