Intracerebroventricular administration of CYX-6, a potent μ-opioid receptor agonist, a δ- and κ-opioid receptor antagonist and a biased ligand at μ, δ & κ-opioid receptors, evokes antinociception with minimal constipation and respiratory depression in rats in contrast to morphine

Novel Cyclic Endomorphin Analogues with Multiple Modifications and Oligoarginine Vector Exhibit Potent Antinociception with Reduced Opioid-like Side Effects

“…The above observations demonstrated that combined chemical modifications of EMs would be helpful in improving their analgesic profiles with reduced unwanted opioid-like side effects. It was recently reported that the EM-2 derivative CYX-6 evoked potent antinociception with minimal constipation and respiratory depression . Novel macrocyclic tetrapeptide cyclo­[Pro-Sar-Phe- d -Phe], a mixed opioid receptor agonist-antagonist, shows great promise for both the treatment of pain with reduced side effects and substance abuse and preventing both drug- and stress-induced relapse in morphine-abstinent subjects. , Zadina el al .…”

Analgesic Opioid Ligand Discovery Based on Nonmorphinan Scaffolds Derived from Natural Sources

“…In other work, CYX-6 (Dmt-Pro-Tmp-Tmp-NH 2 ) ( 98 ) (Figure ) produced an interesting profile as a potent MOP agonist with DOP and KOP antagonist activities in the cAMP assay . In a rat model of nociceptive pain, icv CYX-6 ( 98 ) evoked potent dose-dependent naloxone-sensitive antinociception, confirming that antinociception was opioid-receptor-mediated . No gastrointestinal adverse effects were observed with icv CYX-6 ( 98 ) as measured by the inhibition of gastrointestinal transit or castor oil induced-diarrahea (constipation assays), in contrast to icv morphine ( 1 ) (Figure ).…”

Novel Dual-Target μ-Opioid Receptor and Dopamine D3 Receptor Ligands as Potential Nonaddictive Pharmacotherapeutics for Pain Management

“…The desired product was obtained as colorless oil (640 mg, 91% yield). 1 4-(7-Cyano-3,4-dihydroisoquinolin-2(1H)-yl)-N,N-dimethyl-2,2diphenylbutanamide (24). The reaction was performed following the same procedure described for 23, starting from 1,2,3,4-tetrahydroisoquinoline-7-carbonitrile (100 mg, 0.63 mmol).…”

“…Design, synthesis, and pharmacological characterization of signaling-pathway-biased agonists targeting the MORs allowed the identification of highly selective G-protein-biased agonists, with limited activation of β-arrestin pathways, highlighting different physiological effects mediated by each independent pathway. , It has been suggested that the MOR G-protein pathway seems to be the predominant mediator of the analgesic effects of MOR agonists; meanwhile, it has been posited that the simultaneous hindering of β-arrestin recruitment might reduce the respiratory depression and other side effects, such as constipation, associated with opioid-like drugs. − However, this has been a topic of intensive investigation, and recently, it has been reported that classical MOR agonists, such as morphine and fentanyl , induce dose-dependent respiratory depression and constipation in β-arrestin-2 knock-out mice, similar to what is observed in wild-type mice. − Subsequent pharmacological evaluation has also shown that MOR G-protein-biased agonists still have abuse potential. ,− It is still unclear whether the optimal outcome and pharmacotherapeutic potential of MOR agonists can be gained through selective activation of a particular downstream signaling pathway (functional selectivity) or whether an optimal level partial agonism at multiple pathways may instead provide a route for the development of safer opioids. , Independent of the signaling pathways and cellular mechanisms associated with respiratory depression and constipation, abuse liability remains as a serious concern that must be addressed with different drug design approaches.…”