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Molecules (Basel, Switzerland) Aug 2022Although opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common drugs used in persistent pain treatment; they have shown many side effects. The...
Although opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common drugs used in persistent pain treatment; they have shown many side effects. The development of new analgesics endowed with mu opioid receptor/delta opioid receptor (MOR/DOR) activity represents a promising alternative to MOR-selective compounds. Moreover, new mechanisms, such as sigma-1 receptor (σR) antagonism, could be an opioid adjuvant strategy. The in vitro σR and σR profiles of previous synthesized MOR/DOR agonists (-)-2/-LP2 (), (-)-2-LP2 (), and (-)-2-LP2 () were assayed. To investigate the pivotal role of -normetazocine stereochemistry, we also synthesized the (+)-2/-LP2 (), (+)-2-LP2 (), and (+)-2-LP2 () compounds. (-)-2/-LP2 (), (-)-2-LP2 (), and (-)-2-LP2 () compounds have Ki values for σ1R ranging between 112.72 and 182.81 nM, showing a multitarget opioid/σ1R profile. Instead, (+)-2/-LP2 (), (+)-2-LP2 (), and (+)-2-LP2 () isomers displayed a nanomolar affinity for σ1R, with significative selectivity vs. σ2R and opioid receptors. All isomers were evaluated using an in vivo formalin test. (-)-2-LP2, at 0.7 mg/kg i.p., showed a significative and naloxone-reversed analgesic effect. The σ1R selective compound (+)-2/-LP2 (), at 5.0 mg/kg i.p., decreased the second phase of the formalin test, showing an antagonist σ1R profile. The multitarget or single target profile of assayed -normetazocine derivatives could represent a promising pharmacological strategy to enhance opioid potency and/or increase the safety margin.
Topics: Analgesics; Analgesics, Opioid; Cyclazocine; Humans; Narcotic Antagonists; Pain; Receptors, Opioid, mu; Receptors, sigma; Sigma-1 Receptor
PubMed: 36014375
DOI: 10.3390/molecules27165135 -
Molecules (Basel, Switzerland) Jun 2023In this work, we report on the in vitro and in vivo pharmacological properties of LP1 analogs to complete the series of structural modifications aimed to generate...
In this work, we report on the in vitro and in vivo pharmacological properties of LP1 analogs to complete the series of structural modifications aimed to generate compounds with improved analgesia. To do that, the phenyl ring in the -substituent of our lead compound LP1 was replaced by an electron-rich or electron-deficient ring and linked through a propanamide or butyramide spacer at the basic nitrogen of the (-)---normetazocine skeleton. In radioligand binding assays, compounds and were found to display nanomolar binding affinity for the μ opioid receptor (MOR) (K = 5.96 ± 0.08 nM and 1.49 ± 0.24 nM, respectively). In the mouse vas deferens (MVD) assay, compound showed an antagonist effect against DAMGO ([D-Ala, N-MePhe, Gly-ol]-enkephalin), a highly selective MOR prototype agonist, whereas compound produced naloxone reversible effect at MOR. Moreover, compound , as potent as LP1 and DAMGO at MOR, was able to reduce thermal and inflammatory pain assessed by the mouse tail-flick test and rat paw pressure thresholds (PPTs) measured by a Randall-Selitto test.
Topics: Male; Rats; Mice; Animals; Analgesics, Opioid; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Ligands; Receptors, Opioid, mu; Cyclazocine; Pain
PubMed: 37375382
DOI: 10.3390/molecules28124827 -
Frontiers in Psychiatry 2021Opioids and stimulants are often used in combination for both recreational and non-recreational purposes. High-efficacy mu opioid agonists generally increase the...
Opioids and stimulants are often used in combination for both recreational and non-recreational purposes. High-efficacy mu opioid agonists generally increase the behavioral effects of stimulants, whereas opioid receptor antagonists generally attenuate the behavioral effects of stimulants; however, less is known regarding the interactions between stimulants and opioids possessing low to intermediate efficacy at the mu receptor. The purpose of this study was to examine the role of an opioid's relative efficacy at the mu receptor in altering the behavioral effects of dextro(-)amphetamine. To this end, opioids possessing a range of relative efficacy at the mu receptor were examined alone and in combination with cumulative doses of -amphetamine on a test of open-field, locomotor activity in male rats. Levorphanol, buprenorphine, butorphanol, nalbuphine, (-)-pentazocine, (-)-metazocine, (-)-cyclazocine, (-)-NANM, and nalorphine increased the locomotor effects of -amphetamine in either an additive or greater-than-additive manner according to an effect-additive model. Only the selective, high-efficacy kappa agonist, spiradoline, and the non-selective opioid receptor antagonist, naloxone, failed to increase the effects of -amphetamine under the conditions examined. These data indicate that opioids possessing a large range of relative efficacy at the mu receptor, including those possessing very low relative efficacy, significantly increase the locomotor effects of -amphetamine.
PubMed: 35069292
DOI: 10.3389/fpsyt.2021.790471