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CNS Receptors for Opioids
Published in Edythe D. London, Imaging Drug Action in the Brain, 2017
Richard J. Knopp, Mary Hunt, James K. Wamsley, Henry I. Yamamura
Opioid ligand interactions with the μ1 receptor subtype are defined by radioligand binding studies, which have been used to demonstrate that many opioid ligands bind to a very high affinity site in brain tissue with equilibrium dissociation constants (Kd) in the picomolar range and receptor density values of 0.2 to 3.8 fmol/mg protein. Radioligands exhibiting such binding include [3H]ethylketocyclazocine (Pasternak, 1980), [3H]dihydromorphine (Spiegel and Pasternak, 1984; Recht and Pasternak, 1987), and [3H]DSLET (Itzhak and Pasternak, 1987). Interaction with a high affinity site have also been observed by radioligand binding inhibition studies using unlabeled ligands, including enkephalins (Zhang and Pasternak, 1981), morphiceptin (Zhang et al., 1981), DAMGO (Lutz et al., 1984), and phencyelidine derivatives (Johnson et al., 1984). The conclusion that the high affinity site revealed by such studies represents a common receptor is suggested by the ability of naloxazone and/or naloxonazine treatment to block this binding component while apparently not affecting lower affinity binding sites (Pasternak, 1980; Zhang and Pasternak, 1981; Zhang et al., 1981).
The Role of Neuropeptides in the Normal and Pathophysiological Control of Blood Flow
Published in Edwin E. Daniel, Neuropeptide Function in the Gastrointestinal Tract, 2019
Various physiological and pharmacological experiments using intact animals and isolated tissues indicate that opioids are capable of activating at least four different types of opiate receptors (for a review see Reference 175). Generally, enkephalins are more potent agonists of the δ-receptor, whereas morphine and its related compounds are more selective for the μ-receptor.176 In this regard, the synthetic opioids RX783006177 (termed DAGO) and morphiceptin176 are highly selective for the μ-receptor, whereas d-Ala2,d-Leu5-enkephalin (DADL) and d-Pen2,d-Pen5-enkephaline are selective agonists of the δ-receptor.178 There are no highly selective agonists for the κ receptor. However, benzomorphans, such as ketocyclazocine and bremazocrine, are thought to be more selective at this as opposed to other opioid receptor sites,179,180 whereas the agonist SKF10,047 is thought to be selective for the σ-opioid receptor.180 Radioactive ligand binding studies have demonstrated the presence of δ-, μ-, κ-, and σ-receptors within the human brain,181 and pharmacological studies involving the ileum and vas deferens of various species have demonstrated the presence of δ-, μ-, and κ-receptors on SMCs.77,175,177,182 Selective antagonists for the individual receptors have not been developed yet. However, naloxone in low concentrations can act selectively at the μ-receptor, whereas the antagonist MR2266 can bind selectively to μ- and κ-receptors while diprenorphine has high binding affinities to μ-, δ-, and κ-receptor sites.182
How can we develop better antispasmodics for irritable bowel syndrome?
Published in Expert Opinion on Drug Discovery, 2019
Sheyda Ranjbar, Seyed Afshin Seyednejad, Shekoufeh Nikfar, Roja Rahimi, Mohammad Abdollahi
The opioid system contributes to the modulation of motor and secretory activity of GI through four major opioid receptors mu (MOR), kappa (KOR), delta (DOR) and nociceptin (NOR) [47,48]. MOR agonists decrease GI transit and secretion. Loperamide, a well-known anti-diarrheal opioid, exerts its effects by activating MOR. On the other hand, KOR and DOR are involved in visceral perception and activating these receptors provides anti-nociceptive and even anti-depressant effects [49]. Eluxadoline is a mixed MOR and KOR agonist and DOR antagonist that was approved for IBS-D patients [50]. Inhibiting DOR modulates the motility inhibitory effects exerted through activating MOR and prevents constipation or increased sphincter tone. Therefore, eluxadoline improves patients’ bowel movement frequency without constipating adverse effects and lightens their abdominal pain. Biphalin, an octapeptide encephalin analogue, is a mixed MOR/DOR agonist that inhibited colonic and ileum SMCs contraction in vitro and also the GI motility in a mouse IBS-D model [49]. It was also significantly effective in relieving abdominal pain in a mouse model [51]. Altogether, these features suggest biphalin as a suitable agent for further evaluation in IBS-D patients. In addition, two novel agents, an oral cyclic derivative of morphiceptin (P-317) [52] and a novel mixed MOR/NOR agonist (BU08070), produced significant antidiarrheal and analgesic effects in separate studies on mouse models mimicking symptoms of IBS-D [53,54].