Benzodiazepines partial agonists

Partial agonists at benzodiazepine receptors As discussed for general anxiolytic agents in Chapter 8, the partial benzodiazepine agonists could be a theoretical advance over the marketed benzodiazepines. Partial agonists should have the same efficacy as full agonists but less potential for sedation, dependence, and withdrawal effects. 

The benzodiazepines currently available for clinical use vary substantially in pharmacokinetics, acute euphoriant effects, and frequency of reported dependence. It is likely, therefore, than not all benzodiazepines have the same potential for abuse. Diazepam, lorazepam, and alprazolam may have greater abuse potential than chlordiazepoxide and clorazepate (Wolf et al. 1990). Similarly, oxazepam has been reported to produce low levels of abuse (Eliding 1978). Jaffe et al. (1983) found that in recently detoxified alcoholic patients, halazepam produces minimal euphoria even at a supratherapeutic dosage. The development of partial agonist and mixed agonist/antagonist compounds at the benzodiazepine receptor complex may offer an advantage over approved benzodiazepines for use in alcoholic patients. 

Benzodiazepines have a low risk for abuse in anxiety disorder patients without a history of alcohol or other substance abuse. Among the benzodiazepines there may be a spectrum of abuse liability, with drugs that serve as prodrugs for desmethyldiazepam (e.g., clorazepate), slow-onset agents (e.g., oxazepam), and partial agonists (e.g., abecarnil) having the least potential for abuse. However, there is no currently marketed benzodiazepine or related drug that is free of potential for abuse. 

Perhaps the most studied constituent of passionflower is the flavonoid chrysin. Chiysin was isolated from P. coeruiea, a species closely related to P. incarnata. It binds to benzodiazepine receptors with micromolar affinity (Ki = 3 pM) and competes for binding with the benzodiazepine flunitrazepam (Medina et al. 1990). Behavioral assays (see below) suggest that chrysin acts as a partial agonist at central benzodiazepine receptors (Wolfman et al. 1994). 

Benzodiazepine partial inverse agonist MEM 1003 Memory Pharmaceuticals... 

Buspirone (Buspar). The first nonsedating, nonbenzodiazepine specifically introduced as an anxiolytic, buspirone is FDA approved for the treatment of GAD. This medication acts as a partial agonist at the postsynaptic serotonin (5HT)-1A receptor. Like the antidepressants, buspirone has a delayed onset of action and effectively relieves the intrapsychic symptoms of GAD. Devoid of the muscle-relaxing properties of benzodiazepines, buspirone does not as effectively relieve the physical symptoms of GAD. Buspirone is not effective in the treatment of depression. Furthermore, its utility for the treatment of anxiety disorders other than GAD appears to be limited. 

The search for viable partial agonists or subtype selective ligands has led to the development of a variety of compounds representing diverse structural types including imidazoquinoxalines, benzodiazepines, imidazopyridines and -carbolines. In an effort to identify replacement candidates for the partial agonist pandiplon U 78875 206 [289], which was removed from clinical trials due to... 

A series of imidazo[l,5-a]quinoxaline amides, carbamates, and ureas which have high affinity for the y-aminobutyric acid A/benzodiazepine receptor complex was developed. Compounds within this class have varying activities ranging from antagonists to full agonists. However, most analogs were found to be partial agonists as indicated by [ S]TBPS and Cl current ratios. Many of these... 

Generalized anxiety disorder is still considered the gold standard indication for benzodiazepines (P. J. Perry et al. 1990]. However, buspirone, a serotonin-la partial agonist, has been demonstrated as effective in this disorder... 

This section describes the partial agonists and the nonbenzodiazepine drugs that act at the benzodiazepine receptor. What these drugs have in common is that their development has been driven by the search for effective anxiolytics that do not have the adverse effects of sedation, amnesia, ataxia, interaction with alcohol, or the problems of tolerance, dependency, and withdrawal seen with classic benzodiazepines. These problems have been addressed by the development of partial agonists, subtype-selective ligands, and other drugs, the cyclopyrrolones, which do not seem to cause these problems. 

Pazinaclone. Pazinaclone is a nonbenzodiazepine partial agonist. Animal work has shown that it has anxiolytic and anticonvulsant activity. Pazinaclone does not, however, produce the sedative, muscle relaxant, or motor coordination effects seen with diazepam (Waka and Fukada 1991). Phase II clinical trials are currently under way in the United States, Europe, and Japan, which have so far demonstrated that it is well tolerated and seems to cause significantly less sedation than do benzodiazepines (Uchiumi et al. 1992). 

Alpidem. Alpidem is an imidazopyridine partial agonist that also shows relative selectivity for the type I benzodiazepine receptor. Studies have shown an anxiolytic effect comparable with the classic benzodiazepines, but with an improved adverse effect profile [Pancheri et al. 1993). It has also been compared with buspirone in patients with generalized anxiety disorder and shown to be more rapidly effective and again to have a more favorable adverse effect profile [Legris et al. 1993). Longer-term studies with alpidem have shown that tolerance does not occur, and no significant problems of withdrawal on discontinuation were found [Chevalier et al. 1993). Alpidem was licensed in France for the treatment of anxiety but has now been suspended because of recent reports of alpidem-induced hepatic dysfunction. The reason for this is unclear, but it may be a reflection of the fact that alpidem also binds to peripheral benzodiazepine receptors, which are present in high density in the liver. 

Potokar J, Nutt DJ Anxiolytic potential of benzodiazepine receptor partial agonists. CNS Drugs 1 305-315, 1994... 

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