The binding of 3H-enkephalin (methionine-enkephalin) to membranes of rat brain is inhibited by enkephalin and levorphanol with IC50 values of 5 and 1.6 nM, respectively. Dextrorphan, the optical isomer of levorphanol, is over 6,000 times less effective. Opiate agonists, morphine, dihydromorphine and l-methadone and opiate antagonists, naltrexone and naloxone are less effective inhibitors of 3H-enkephalin than in 3H-dihydromorphine and 3H-naloxone binding. However, opiates without the oxygen bridge as in the structure of morphine, such as levorphanol and the benzomorphans show affinities for the receptors of 3H-enkephalin equal or greater than their affinities for the receptors of 3H-opiates.
Pergolide (LY127809, CAS 66104-23-2), pergolide sulfone and pergolide sulfoxide inhibited 3H-dopamine binding to dopamine receptors in bovine striatal membranes with Ki values of 2.5, 4.6 and 15.5 nmol/l, respectively. Despropyl pergolide and despropyl pergolide sulfoxide are not as potent, with Ki values of 58.6 and 158.8 nmol/l, respectively. The derivatives of pergolide inhibit the binding of antagonist ligands 3H-Sch23390 and 3H-Spiperone to D1 and D2 dopamine receptors, respectively, in bovine striatal membranes with higher Ki concentrations. Upon administration to rats, pergolide sulfoxide and sulfone were as effective as pergolide in increasing acetylcholine levels and decreasing the metabolites of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels in striatum, while the despropyl derivatives of pergolide and pergolide sulfoxide were only marginally effective in increasing acetylcholine levels in striatum.
Xanomeline [3(3-hexyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1- methylpyridine] has been evaluated as a muscarinic receptor agonist. In vitro, xanomeline had high affinity for muscarinic receptors in brain homogenates, but had substantially less or no affinity for a number of other neurotransmitter receptors and uptake sites. In cells stably expressing genetic m1 receptors, xanomeline increased phospholipid hydrolysis in CHO, BHK and A9 L cells to 100, 72 and 55% of the nonselective agonist carbachol. In isolated tissues, xanomeline had high affinity for M1 receptors in the rabbit vas deferens (IC50 = 0.006 nM), low affinity for M2 receptors in guinea pig atria (EC50 = 3 microM), was a weak partial agonist in guinea pig ileum and was neither an agonist nor antagonist in guinea pig bladder. In vivo, xanomeline increased striatal levels of dopamine metabolites, presumably by acting at M1 heteroreceptors on dopamine neurons to increase dopamine release. In contrast, xanomeline had only a relatively small effect on acetylcholine levels in brain, indicating that it is devoid of actions at muscarinic autoreceptors. In the gastrointestinal tract, xanomeline inhibited small intestinal and colonic motility, but increased small intestinal transmural potential difference. In contrast to the nonselective muscarinic agonist oxotremorine, xanomeline did not produce salivation, tremor nor hypothermia; it did, however, increase heart rate. The present data are consistent with the interpretation that xanomeline is a novel muscarinic receptor agonist with functional selectivity for M1 muscarinic receptors both in vitro and in vivo.
Fluoxetine prevents the loss of 5-hydroxytryptamine (5HT) uptake in synaptosomes of cerebral cortex after intraperitoneally administered p-chloroamphetamine (p-CA) with an ED50 of 3.8 mg/kg i.p. in rats. However, at 50 mg/kg, it does not prevent the loss of norepinephrine (NE) uptake in synaptosomes of hypothalamus after intraventricularly administered 6-hydroxydopamine (6-OHDA). Nisoxetine, on the other hand, centrally protects NE uptake from the neurotoxic effect of 6-OHDA with an ED50 value of 5 mg/kg i.p. At 50 mg/kg, it gives only 35% protection of 5HT uptake from the neurotoxic effect of p-CA. In comparison with the ED50 values of tricyclic antidepressants, both fluoxetine and nisoxetine are more potent and selective blockers of neurotoxicity resulting from the central actions of p-CA and 6-OHDA, respectively, in vivo.
The optical isomers of methadone, alpha-methadol, alpha-acetylmethadol and their N-demethylated derivatives have been systematically studied for their effects on the binding of 3H-dihydromorphine (3H-DHM) and 3H-naloxone (3H-NLX) to opiate receptors in rat brain homogenate. The relative affinities of these agents in competing for both 3H-DHM and 3H-NLX binding parallel their analgesic effects. 1-Methadone is about 30 times as effective as d-methadone in competing for both 3H-DHM and 3H-NLX binding sites. The reduction of 1-methadone to alpha-d-methadol and subsequent N-demethylation to alpha-d-normethadol reduce its effectiveness as indicated by the increase in the IC50 values for both 3H-DHM and 3H-NLX binding. The reduction of d-methadone followed by N-demethylation produces a potent derivative, alpha-1-normethadol, which has IC50 values on 3H-DHM and 3H-NLX binding similar to those of 1-methadone. The affinity of alpha-1-acetyl-methadol on the binding of both 3H-ligands falls between those of 1-methadone and d-methadone, and increases as it is N-demethylated. alpha-d-Acetyl-methadol is more effective than alpha-1-acetylmethadol in competing for both 3H-ligands from the opiate receptors, and its affinity, unlike that of alpha-1-acetylmethadol, decreases when it is N-demethylated. The affinities of the methadone isomers and related compounds on the binding of 3H-NLX fall in the presence of Na+. The latter property indicates the agonistic nature of this series of druges.
Binding of [3H]-serotonin ([3H]5-hydroxytryptamine, [3H]5HT) to high and low affinity sites in brain membranes from frontal cortex was compared in rats fed control chow or fluoxetine (0.01%) containing chow. A reduction in the number of high affinity binding sites and in the affinity of the low affinity binding sites was observed after 2, 4 or 6 weeks. Reduction in the number of [3H]5HT binding sites was also observed in cerebral cortex of rats given fluoxetine by daily intraperitoneal injection for 4 or 6 weeks. Thus, long-term treatment with a selective inhibitor of serotonin uptake, fluoxetine, caused subsensitivity of 5HT receptors in frontal cortex and cerebral cortex of rat brain.
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