Opioids, agonist activity

Pharmacology Nalmefene, an opioid antagonist, is a 6-methylene analog of naltrexone. Nalmefene prevents or reverses the effects of opioids, including respiratory depression, sedation, and hypotension. Nalmefene has no opioid agonist activity it does not produce respiratory depression, psychotomimetic effects or pupillary constriction, and no pharmacological activity was observed when it was administered in the absence of opioid agonists. Nalmefene can produce acute withdrawal symptoms in individuals who are opioid-dependent. 

As for any difference between the rates of cocaine abuse in individuals on methadone and buprenorphine, there is a theoretical consideration that perhaps less cocaine use can be expected on the latter because of a reduced mutually reinforcing ( speedball ) effect with only partial opioid agonist activity, and some empirical support for this (Foltin Fischman 1996, Giacomuzzi et al. 2003). However, Schottenfeld et al. (2005) found superiority of methadone over buprenorphine in treatment retention and periods of abstinence in their cocaine-abusing opioid patients. 

The opioid agonistic activities of ( )-TAN-67, its derivatives 71d and 71f, and DPDPE were evaluated on electrically stimulated guinea-pig ileum (GPI) and mouse vas deferens (MVD) preparations (Table 4) [34,36]. It is known that ix and k opioid receptors are predominantly expressed in GPI and the 8 receptor is predominantly expressed in MVD [37,38]. The IC50 value is the index of agonistic activity—the smaller its value, the more potent the agonistic... 

Heterocycles were explored as replacements for the nonphenolic ring (Table 3) [19]. Unsubstituted thiazoles, pyridines, and thiophenes gave active agonists, but with little or no selectivity. While an TV-methyl imidazole had little if any opioid agonist activity in this series, often additional substituents on the heterocycles provided potent compounds with delta opioid receptor selectivity. For instance, compound 34, a thiophene with a diethyl carboxamide, displayed selective delta opioid receptor agonism (although no binding selectivity was observed). 

The requirement for a basic amine group for 6-opioid agonist activity (in this case the distance of the amine group relative to the two aromatic groups was not optimized). 

Opioid agonist activity decreased Opioid antagonist activity increased Inactive as opioid agonist or antagonist... 

Diphenoxylate HCI (2.5 mg) and atropine (0.025 mg) are combined in tablets or 5 mL liquid and are used effectively as symptomatic treatment for diarrhea. The typical dose is two tablets or 10 mL every 3 to 4 hours. The combination with atropine enhances the block of acetylcholine-stimulated peristalsis, and the adverse effects of atropine helps to limit the abuse of the opioid. The combination is Schedule V under the Controlled Substances Act. Diphenoxylate itself has low p opioid agonist activity. It is metabolized rapidly by ester hydrolysis to the zwitterionic free carboxylate (difenoxin), which is five times more potent after oral dosing. The zwitterionic properties of difenoxin probably limits its penetration into the CNS and explains the low abuse potential of this agent. High doses of diphenoxylate (40-60 mg) will cause euphoria and addiction. 

The introduction of a hydroxy group at C-14 afforded cis and trans isomers (P and a in optically active compounds). Studies carried out mostly with racemic mixtures are incomplete (Belleau 1982). A great number of 14-j3-OH substituted ketomor-phinans were evaluated (Rahman and Brossi 1977, Seki et al. 1964, Schmidhammer et al. 1981) and it was found that ]8-hydroxylation at C-14 did not drastically alter the opioid agonist activity. Conversion of a 14-j3-OH into a 14-]3-OMe group, on the other hand, afforded compounds with very high antinociceptive potency accompanied by considerable opioidtype side-effects (Schmidhammer et al. in press). 

This method has been exploited in a synthetic sequence leading to salvinorin A that shows potent K opioid agonist activity. Alkenyl sulfrdes can also be employed as electrophiles in iron-catalyzed cross-coupling reactions with Grignard reagents (Scheme 4-215). The reaction is chemoselective for alkenyl sulfides, whereas aryl sulfides show only very low reactivity. ... 

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