The reverse transcriptase-polymerase chain reaction (RT-PCR) was used to clone a cDNA fragment of a putative G-protein-coupled receptor from rat brain total RNA. Nucleotide sequencing of this cDNA fragment showed it to be homologous to that of the mu-opioid receptor splice variant MOR(1C) from mice. We used the cDNA to make an RNA probe for a ribonuclease protection assay (RPA). The results from the RPA showed a protected fragment of the size expected for MOR(1C) mRNA, as well as other RNase-protected fragments that may indicate the existence of other MOR1 transcripts. We then used the RNA probe for in situ hybridization (ISH) experiments. We detected strong autoradiographic labeling over much of the rat telencephalon, diencephalon, mesencephalon, cerebellum, spinal cord, and dorsal root ganglia. These findings suggest that MOR(1C), and possibly other MOR1 splice variants, are important components of the system by which the actions of opioids are transduced.
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http://dx.doi.org/10.1002/cne.20103 | DOI Listing |
Fentanyl is a potent synthetic opioid widely used perioperatively and illicitly as a drug of abuse . It is well established that fentanyl acts as a μ-opioid receptor agonist, signaling through Gα intracellular pathways to inhibit electrical excitability, resulting in analgesia and respiratory depression . However, fentanyl uniquely also triggers muscle rigidity, including respiratory muscles, hindering the ability to execute central respiratory commands or to receive external resuscitation.
View Article and Find Full Text PDFLarge library docking of tangible molecules has revealed potent ligands across many targets. While make-on-demand libraries now exceed 75 billion enumerated molecules, their synthetic routes are dominated by a few reaction types, reducing diversity and inevitably leaving many interesting bioactive-like chemotypes unexplored. Here, we investigate the large-scale enumeration and targeted docking of isoquinuclidines.
View Article and Find Full Text PDFBioorg Med Chem Lett
January 2025
Contineum Therapeutics, 3565 General Atomics Court, Suite 200, San Diego, CA 92121, United States.
Novel kappa opioid receptor (KOR) agonists that preferentially activate G-protein signaling versus β-arrestin-2 recruitment are described. Starting from a literature-reported phenol-containing diphenethylamine KOR agonist, structure-activity relationship (SAR) studies revealed replacement of the phenol with various non-hydroxylated bicyclic heteroaromatics led to tertiary diarylethylamines which retained KOR agonist activity and improved metabolic stability in human liver microsomes. Further optimizations produced compound 39, a potent activator of G-protein signaling (GTPγS EC = 14 nM, 83 % E) that did not elicit a β-arrestin-2 recruitment functional response (E < 10 %).
View Article and Find Full Text PDFPharmaceuticals (Basel)
January 2025
Department of Biotechnology and Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766, USA.
There is clinical concern about the combined use of alcohol and opiates. Several lines of evidence support an interaction between alcohol and the endogenous opioid system. Thus, we hypothesized that ethanol, by causing the release of opioid peptides, may sensitize the system to the action of exogenous opioids such as morphine.
View Article and Find Full Text PDFACS Chem Neurosci
January 2025
Center for Basic Medical Research, Medical School of Nantong University, Nantong 226001, P. R. China.
Chronic pain is a debilitating disease and remains challenging to treat. Morphine serves as the most commonly used drug for the treatment of pathological pain. However, detrimental side effects (e.
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