Pharmacologic Characterization of Substituted Nitazenes at , , and Opioid Receptors Suggests High Potential for Toxicity.

The benzimidazole opioids (substituted nitazenes) are highly potent opiod receptor (MOR) agonists with heroin- or fentanyl-like effects. These compounds have caused hospitalizations and fatal overdoses. We characterized the in vitro pharmacology and structure-activity relationships of 19 nitazenes with substitutions at three positions of the benzimidazole core.

Enantiomeric Separation, Absolute Configuration by X-ray Crystallographic Analysis, and Functional Evaluation of Enantiomers of the Dual Ligand, SYA0340 at 5-HT and 5-HT Receptors.

We have previously identified 5-chloro-2-methyl-2-(3-(4-(pyridin-2-yl)piperazin-1-yl)propyl)-2,3-dihydro-1-inden-1-one (SYA0340) as a dual 5-HT and 5-HT receptor ligand, and we posited such ligands might find utility in the treatment of various CNS related illnesses including cognitive and anxiolytic impairments. However, SYA0340 has a chiral center and its enantiomers may confound the readouts for their functional characteristics. Thus, in this study, we resynthesized SYA0340, separated the enantiomers, identified the absolute configurations, and evaluated their binding affinities and functional characteristics at both the 5-HT and 5-HT receptors.

Pharmacologic Activity of Substituted Tryptamines at 5-Hydroxytryptamine (5-HT) Receptor (5-HTR), 5-HTR, 5-HTR, and Serotonin Transporter.

Novel psychoactive substances, including synthetic substituted tryptamines, represent a potential public health threat. Additionally, some substituted tryptamines are being studied under medical guidance as potential treatments of psychiatric disorders. Characterizing the basic pharmacology of substituted tryptamines will aid in understanding differences in potential for harm or therapeutic use.

A highly DR-selective and efficacious partial agonist (S)-ABS01-113 compared to its DR-selective antagonist enantiomer (R)-ABS01-113 as potential treatments for opioid use disorder.

The non-medical use of opioids has become a national crisis in the USA. Developing non-opioid pharmacotherapies for controlling this opioid epidemic is urgent. Dopamine D receptor (DR) antagonists and low efficacy partial agonists have shown promising profiles in animal models of opioid use disorders (OUD).

New dual 5-HT1A and 5-HT7 receptor ligands derived from SYA16263.

We have previously reported that dual 5-HT and 5-HT receptor ligands might find utility as treatment options for various CNS related conditions including cognitive and anxiolytic impairments. We have also more recently reported that SYA16263 has antipsychotic-like properties with an absence of catalepsy in animal models ascribed to its ability to recruit β-arrestin to the D receptor. However, SYA16263 also binds with very high affinity to 5-HTR (Ki = 1.

Fentanyl but not Morphine Interacts with Nonopioid Recombinant Human Neurotransmitter Receptors and Transporters.

Synthetic opioids, including fentanyl and its analogs, have therapeutic efficacy in analgesia and anesthesia. However, their illicit use in the United States has increased and contributed to the number one cause of death for adults 18-50 years old. Fentanyl and the heroin metabolite morphine induce respiratory depression that can be treated with the opioid receptor (MOR) antagonist naloxone.