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Interactions of trimebutine with guinea-pig opioid receptors
Abstract:
Affinities of trimebutine (TMB) and N-desmethyl trimebutine (NDTMB) for mu, delta and kappa opioid receptor subtypes have been examined using specific 3H-ligands and guinea-pig membrane. TMB and NDTMB showed a relative higher affinity for the mu receptor subtype although they were, respectively, 30- and 48-fold less active than morphine. The receptor selectivity index for mu, delta and kappa were 100:12:14.4 for TMB, 100:32:25 for NDTMB and 100:5:5 for morphine. The sodium shift ratio was 14 for TMB, 10 for NDTMB and 37 for morphine. These data show that (unlike morphine, a pure mu agonist) TMB and NDTMB can be classified as weak opioid agonists and confirm that peripheral opioid receptors mediate their gastrointestinal motility effects.
Insights
Trimebutine (TMB) and its metabolite N-desmethyl trimebutine (NDTMB) are weak opioid agonists with higher affinity for mu receptors. Peripheral opioid receptors mediate their gastrointestinal effects.
Area of Science:
- Pharmacology
- Gastroenterology
- Neuroscience
Background:
- Trimebutine (TMB) and its active metabolite N-desmethyl trimebutine (NDTMB) are commonly used to treat gastrointestinal motility disorders.
- Opioid receptors, including mu, delta, and kappa subtypes, play a significant role in regulating gastrointestinal function.
Purpose of the Study:
- To investigate the binding affinities of TMB and NDTMB to mu, delta, and kappa opioid receptor subtypes.
- To characterize the opioid receptor interaction profile of TMB and NDTMB and compare it to morphine.
Main Methods:
- Radioligand binding assays using specific 3H-ligands were performed on guinea-pig membrane preparations.
- Affinity and selectivity for opioid receptor subtypes were determined.
- Sodium shift ratios were measured to assess functional activity.
Main Results:
- TMB and NDTMB exhibited higher affinity for the mu opioid receptor subtype compared to delta and kappa subtypes.
- TMB and NDTMB were less potent than morphine at the mu receptor, showing 30-fold and 48-fold lower activity, respectively.
- Receptor selectivity indices indicated a distinct binding profile for TMB and NDTMB compared to morphine, with TMB (100:12:14.4) and NDTMB (100:32:25) showing different selectivity patterns than morphine (100:5:5).
- Sodium shift ratios were lower for TMB (14) and NDTMB (10) than for morphine (37), suggesting weaker agonist activity.
Conclusions:
- TMB and NDTMB can be classified as weak opioid agonists, unlike morphine, a pure mu agonist.
- These findings confirm that peripheral opioid receptors are involved in mediating the gastrointestinal motility effects of TMB and NDTMB.