Mixed Agonist-antagonist Properties Research Articles

Triple monoamine uptake inhibitors demonstrate a pharmacologic association between excessive drinking and impulsivity in high-alcohol-preferring (HAP) mice.

Approximately 30% of current drinkers in the United States drink excessively, and are referred to as problem/hazardous drinkers. These individuals, who may not meet criteria for alcohol abuse or dependence, comprise binge, heavy drinkers, or both. Given their high prevalence, interventions that reduce the risk of binge and heavy drinking have important public health implications. Impulsivity has been repeatedly associated with excessive drinking in the clinical literature. As impulsivity is correlated with, and may play a critical role in, the initiation and maintenance of excessive drinking, this behavior may be an important target for therapeutic intervention. Hence, a better understanding of pharmacological treatments capable of attenuating excessive drinking and impulsivity may markedly improve clinical outcomes. The high-alcohol-preferring (HAP) mice represent a strong rodent model to study the relationship between impulsivity and excessive alcohol drinking, as recent evidence indicates they consume high levels of alcohol throughout their active cycle and are innately impulsive. Using this model, the present study demonstrates that the triple monoamine uptake inhibitors (TUIs) amitifadine and DOV 102, 677 effectively attenuate binge drinking, heavy drinking assessed via a 24-hour free-choice assay, and impulsivity measured by the delay discounting procedure. In contrast, 3-PBC, a GABA-A α1 preferring ligand with mixed agonist-antagonist properties, attenuates excessive drinking without affecting impulsivity. These findings suggest that in HAP mice, monoamine pathways may predominate as a common mechanism underlying impulsivity and excessive drinking, while the GABAergic system may be more salient in regulating excessive drinking. We further propose that TUIs such as amitifadine and DOV 102, 677 may be used to treat the co-occurrence of impulsivity and excessive drinking.

Mixed Agonist–Antagonist Properties of Clozapine at Different Human Cloned Muscarinic Receptor Subtypes Expressed in Chinese Hamster Ovary Cells

We recently reported that clozapine behaves as a partial agonist at the cloned human m4 muscarinic receptor subtype. In the present study, we investigated whether the drug could elicit similar effects at the cloned human m1, m2, and m3 muscarinic receptor subtypes expressed in the Chinese hamster ovary (CHO) cells. Clozapine elicited a concentration-dependent stimulation of [3H]inositol phosphates accumulation in CHO cells expressing either the m1 or the m3 receptor subtype. Moreover, clozapine inhibited forskolin-stimulated cyclic AMP accumulation and enhanced [35S] GTPγS binding to membrane G proteins in CHO cells expressing the m2 receptor. These agonist effects of clozapine were antagonized by atropine. The intrinsic activity of clozapine was lower than that of the full cholinergic agonist carbachol, and, when the compounds were combined, clozapine potently reduced the receptor responses to carbachol. These data indicate that clozapine behaves as a partial agonist at different muscarinic receptor subtypes and may provide new hints for understanding the receptor mechanisms underlying the antipsychotic efficacy of the drug.

Mixed agonist-antagonist properties of umespirone at neostriatal dopamine receptors in relation to its behavioral effects in the rat

In normal rats treated with the inhibitor of cerebral decarboxylase, NSD-1015 (100 mg kg −1 i.p.), umespirone (1.9–30.0 μmol kg −1 s.c.) produced an increase in neostriatal DOPA (dihydroxyphenylalanine) accumulation, whereas decreased DOPA accumulation was obtained in reserpine-pretreated (5 mg kg −1 s.c., −18 h) animals. The latter effect was statistically significant only in the ventral, limbic, portion of the neostriatum. Neostriatal 5-hydroxytryptophan (5-HTP) accumulation was decreased in the reserpine-treated animals but not in normal controls. DOPA accumulation in the neocortex was not affected by umespirone treatment in either preparation, whereas 5-HTP accumulation was decreased in the reserpine-treated animals. Spontaneous locomotor activity was suppressed by umespirone at doses that did not affect treadmill locomotion (7.9–31.2 μmol kg −1 s.c., −30 min), and there were no signs of catalepsy at doses ranging from 31.2–249.6 μmol kg −1 s.c. up to 2 h after injection. Thus, umespirone behaves as a mixed dopamine receptor agonist/antagonist and also displays 5-HT receptor agonist properties. This biochemical profile was associated with sedation, as observed in the open-field, at doses which did not affect treadmill locomotion or induced catalepsy.

Evaluation of the anticonvulsant and biochemical activity of CGS 8216 and CGS 9896 in animal models.

CGS 8216, a benzodiazepine-receptor ligand with inverse agonistic properties, and CGS 9896, which possesses partial agonistic or mixed agonist-antagonist properties were compared in a number of epilepsy models. The effect of CGS 9896 on the decrease in GABA levels induced by isoniazid was also investigated. CGS 9896 inhibited the kindling process in rats in that it delayed the development of overt seizures and the increase in the duration of afterdischarges. In a genetic rat model characterized by absence-like EEG patterns, CGS 9896 dose-dependently suppressed these spontaneously occurring discharges, while CGS 8216 had no effect. However, CGS 8216 antagonized the anticonvulsant action of CGS 9896. CGS 9896 protected mice against seizures induced by beta-vinyllactic acid, whereas CGS 8216 shortened the latency period before convulsions occurred. CGS 9896 retarded the onset of convulsive fits caused by isoniazid without preventing the decrease in GABA levels produced by that drug. These results confirm the anticonvulsant activity of CGS 9896 and demonstrate the inverse agonistic activity of CGS 8216. The profile of CGS 9896 in the above tests suggests that it might be an effective anticonvulsant, primarily in absence-type seizures.

Effects of chlordiazepoxide training dose on the mixed agonist-antagonist properties of benzodiazepine receptor antagonist Ro 15-1788, in a drug discrimination procedure

In experiment 1, rats (n = 12) were trained to discriminate the benzodiazepine (BDZ) compound chlordiazepoxide (CDP, 20 mg/kg, IP) from saline in a two-lever food-reinforced procedure, and subsequently were tested for stimulus control with different doses of CDP, Ro 15-1788 (a proposed BDZ receptor antagonist) and Ro 15-1788 plus 20 mg/kg CDP. Ro 15-1788 (0.63-40 mg/kg) dose-dependently antagonized CDP, and induced predominantly saline appropriate responding when administered alone. Thereafter, the same rats were retrained by progressively decreasing the training dose, to discriminate 2.5 mg/kg CDP from saline, and were tested again with the same compounds. Ro 15-1788 (0.16-40 mg/kg) now failed to antagonize CDP (2.5 mg/kg) and increased the percentage of drug-appropriate responding in a dose-related manner when administered alone. In experiment 2, separate groups of rats (n = 10) were similarly trained to discriminate either 15 or 3 mg/kg CDP from saline. Tests with CDP, Ro 15-1788 and Ro 15-1788 plus CDP (either 15 or 3 mg/kg) yielded similar results to experiment 1, suggesting that the training dose effects on generalization and antagonism of Ro 15-1788 were not affected by the manner in which the lower CDP dose acquired drug stimulus control. It is concluded that mixed agonist-antagonist properties are apparent after variations of the BDZ training dose in a drug discrimination procedure.

Picenadol.

Picenadol is a unique opioid mixed agonist-antagonist analgesic currently under clinical evaluation. Structurally, picenadol is a 4-phenylpiperidine derivative and a racemic mixture whose mixed agonist-antagonist properties are a consequence of the d-isomer being a potent opiate agonist, whereas the l-isomer is an opioid antagonist. In the mouse writhing and rat tail heat tests, the analgesic potency of picenadol is estimated to be 1/3 that of morphine. Picenadol itself has weak antagonist activity, whereas the antagonist potency of the l-isomer is approx. 1/10 that of nalorphine. Evaluation of picenadol's affinity for opioid receptors reveals that picenadol, unlike other mixed agonist-antagonists has high affinity for both the mu and delta receptors but a markedly lower affinity for the kappa receptor. Extensive pharmacological investigations show picenadol to have a low potential to produce opiate-like side effects, including a low liability for abuse and physical dependence.

Clinical Pharmacology of Opioid Analgesics

Opioid analgesics continue to be the most important drugs in modifying the response to pain. Their versatility is attested by their frequent use in both postoperative and intraoperative management of pain. Recent findings regarding the mechanism of action of opioids may signal the introduction of newer, more effective, and less addictive agents. So far, this has not occurred. However, opioids with mixed agonist-antagonist properties have offered some utility. The adverse effects of nausea and dysphoria and the more serious effects of respiratory depression continue to be a problem, as does the possibility of abuse. Nonetheless, the clinical experience with opioids in control of pain is uncontested. Until better drugs are developed, opioids will form the basis for the control of acute pain by the dental practitioner.

A trial of meptazinol for the relief of pain after abdominal surgery.

Meptazinol is an opioid drug having mixed agonist-antagonist properties. Chemically it is a hexahydroazepine derivative. It has been used to provide postoperative analgesia for patients undergoing abdominal surgery but only in single dose studies. The drug is of particular interest in that the clinical impression of minimal ventilatory depression has been confirmed, 60 mg meptazinol showing less ventilatory depression than 10 mg of morphine. To test its efficacy in patients undergoing abdominal surgery and to assess the incidence of side effects, an open study was undertaken in 43 patients.

Agonist—antagonist properties of phenoxybenzamine in antinociception and opiate dependence tests

The doe—response curve for phenoxybenzamine inhibition of stereospecific 3H-naloxone binding in brain homogenates was found to shift to the right in the presence of 100 mM NaCl. From the ratios of the IC 50 in the presence of Na + to the IC 50 in the presence of Na + calculated in this study for phenoxybenzine and some opiates it was predicted that phenoxybenzamine would have mixed agonist—antagonist properties in antinociceoption and that its antagonist activity would be in the rank order: butorphanol (1.8) ⪢ phenoxybenzamine (4.3) > M2230 (5.7) > pentazocine (6.9) ⪢ levorphanol (13.6). Phenoxybenzamine antagonized the oxymorphone-induced Straub tail reaction in mice and induced the abstinence syndrome in non-withdrawn morpine-dependent mice as predicted by the Na + response ratio. In the mouse tail flick assay phenoxybenzamine acted like the mized agonist—antagonist benzomorphinas as predicted. In “physical dependence capabilty” phenoxybenzamine was intermediate between butorphanol and pentazocine as predicted by the Na + response ratios. The success of the Na + response ratio derived from phenoxybenzamine's properties in the vitro opiate binding assay in predicting the behavior and rank order of phenoxybenzamine in in vivo tests, plus the ability of naloxone to antagonize phenoxybenzamine's antinociceptive action suggest that phenoxybenzamine's antinociceptive action may be mediated by the brain opiate receptor rather than by central α-adrenergic receptor blockade.

Dihydrocortisol: A potential mineralocorticoid

The finding of abnormal metabolism of cortisol in a low-renin, low-aldosterone, hypertensive child with the stigmata of hypermineralocorticoidism led us to examine the mineralocorticoid activity of several cortisol metabolites. Of these metabolites, dihydrocortisol (DHF) possessed mineralocorticoid activity as determined by several assays. In competition assays with [ 3H]-aldosterone or [ 3H]-dexa-methasone in rat kidney slices, the relative affinities for the respective cytoplasmic receptors were as follows: mineralocorticoid receptor-aldosterone (1.00) > cortisol (0.20) > 5α-DHF (0.083) > 5β-DHF (0.042) and glucocorticoid receptor-dexamethasone (1.00) > cortisol (0.10) > 5α-DHF (0.002) > 5β-DHF (0.001). On the basis of these receptor assays 5α-DHF and possibly 5β-DHF were potential mineralocorticoids but probably weak glucocorticoids. The free serum concentration probably determines the biologically-effective steroid concentration. Accordingly, the affinity of these cortisol metabolites for corticosteroid binding globulin (CBG) was determined as well. In competition assays with [ 3H]-cortisol for binding to purified human CBG, the relative affinities were: cortisol (1.00) > 5 α- DHF (0.083) = 5 β- DHF (0.083). The enhanced free concentration of both cortisol metabolites should allow greater access to cellular receptors. Since binding to receptors does not indicate whether the bound steroid will have agonist, antagonist, or mixed agonist-antagonist properties, the metabolites were further tested in two physiological assays. In the isolated toad bladder, at a concentration 500 × that of aldosterone, cortisol, 5α-DHF and 5β-DHF stimulated active Na + transport measured as the short-circuit current in the following order: aldosterone (1.00) > cortisol (0.80) > 5α-DHF (0.65) > 5β-DHF (none). Infusion of cortisol, 5α- and 5β-DHF into adrenalectomized rats at concentrations 100 × that of aldosterone, produced the following relative changes in K/Na urinary ratios: aldosterone (1.00) > cortisol (0.60) > 5α-DHF (0.38) > 5β-DHF (0.28). Of the observed changes, only the 5β-DHF value was not statistically significant. These results imply that 5α-DHF should be considered a potential mineralocorticoid.