Novel N-Substituted Benzomorphan-Based Compounds: From MOR-Agonist/DOR-Antagonist to Biased/Unbiased MOR Agonists

Abstract

Modifications at the basic nitrogen of the benzomorphan scaffold allowed the development of compounds able to segregate physiological responses downstream of the receptor signaling, opening new possibilities in opioid drug development. Alkylation of the phenyl ring in the N-substituent of the MOR-agonist/DOR-antagonist LP1 resulted in retention of MOR affinity. Moreover, derivatives 7a, 7c, and 7d were biased MOR agonists toward ERK1,2 activity stimulation, whereas derivative 7e was a low potency MOR agonist on adenylate cyclase inhibition. They were further screened in the mouse tail flick test and PGE2-induced hyperalgesia and drug-induced gastrointestinal transit.

Dual Sigma-1 receptor antagonists and hydrogen sulfide-releasing compounds for pain treatment: Design, synthesis, and pharmacological evaluation

“…We also included 2a, DTG ( 9), (+)-pentazocine (10), BD-1063 (11), DAMGO (13), naltrindole ( 14) and ()-U50,488 (15) as internal controls that were tested with the same membrane homogenates of the hybrid compounds under investigation (Figure S1). All the reference compounds showed Ki values for σ1 and σ2 receptors and the three opioid receptors comparable to those reported in previous studies [27][28][29][30][31][32]. It is worth pointing out that compounds 1a,b were devoid of affinity for either σ receptors or the three opioid receptors examined.…”

LP1 and LP2: Dual-Target MOPr/DOPr Ligands as Drug Candidates for Persistent Pain Relief

“…Finally, LP1 analogues variously o / m / p polymethylated at the phenyl ring of the N - substituent, and analogues featured with tertiary N -benzylpropanamide substituents were synthesized ( Figure 2 ) [ 46 ]. Biased and unbiased MOPr agonists toward ERK1,2 activity stimulation and on adenylate cyclase inhibition were obtained.…”

“…Moreover, the LP1 anti-hyperalgesic effect was also rescued through mouse PGE2-induced heat hyperalgesia and compared to morphine ( Figure 8 , panel a) [ 46 ]. In agreement with previous findings, both morphine (1–3 mg/kg, s.c.) and LP1 (1–4 mg/kg, s.c.) induced a dose-dependent increase in paw withdrawal latency in PGE2-treated mice, reaching values similar to those detected in control animals.…”

“…As constipation is known as an opioid-induced side effect [ 54 ], LP1 effects on gastrointestinal transit were also tested ( Figure 8 , panel b) [ 46 ]. Immediately after the evaluation of the behavioral responses to heat stimulus, mice received intragastrically an activated charcoal solution.…”

Design of Analgesic Trivalent Peptides with Low Withdrawal Symptoms: Probing the Antinociceptive Profile of Novel Linear and Cyclic Peptides as Opioid Pan Ligands

“…However, even compounds endowed with high binding affinity for μ-opioid receptor (MOR) and mixed MOR/δ-opioid receptor (DOR) agonists demonstrate unwanted side effects which render them poorly suitable as drug candidates. , Activation of DOR produces spinally mediated antinociception that is enabled by inflammation, which is generally less pronounced than that produced by MOR stimulation; DOR antagonists may also prevent MOR-mediated tolerance development and dependence/withdrawal . The phenomena of reward/reinforcement involve selective DOR agonists with which the presence of MORs is also required to generate reinforcing properties. − …”