Anxiolytics partial agonists

Albert PR, Sajedi N, Lemonde S, Ghahremani MH. Constitutive Ga dependent activation of adenylyl cyclase type II by the 5-HT1A receptor. Inhibition by anxiolytic partial agonists. J Biol Chem 1999 274 35,469-35,474. 

Beginning in the 1960s, ben2odia2epiae anxiolytics and hypnotics rapidly became the standard prescription dmg treatment. In the 1980s, buspkone [36505-84-7] (3), which acts as a partial agonist at the serotonin [50-67-9] (5-hydroxytryptamine, 5-HT) type lA receptor, was approved as treatment for generali2ed anxiety. More recently, selective serotonin reuptake inhibitors (SSRIs) have been approved for therapy of panic disorder and obsessive—compulsive behavior. 

Alternative pharmacological approaches Clonidine, an o2 adrenergic agonist, has been employed as adjunctive therapy to assist in smoking cessation. However, results have been mixed or the effects small (Gourlay et al. 1994 Hilleman et al. 1993 Franks et al. 1989). Buspirone (BuSpar) is a 5-HTlA partial agonist with anxiolytic effects. It has been tested as a treatment for smoking cessation because anxiety is a prominent feature of nicotine withdrawal (Farid and Abate 1998). To date, results have been mixed and more controlled research is needed. 

Other serotonergic drugs that are direct receptor agonists or antagonists have been found to have anxiolytic effects (Stahl 1998 Bonhomme and Esposito 1998). A novel class of anxiolytic drugs called azapirones act as partial agonists at 5-HTlA receptors (Yocca 1990). Clinically, they are represented by BuSpar, which was approved for use in 1986 (Eison... 

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. 

Anxiolytic activity Several novel anxiolytics (e.g. buspirone, ipsapirone) are 5-HTia partial agonists 5-HT2 and 5-HT3 antagonists have anxiolytic properties... 

Kanthan R, Shuaib A (1995) Clinical evaluation of extracellular amino acids in severe head trauma by intracerebral in vivo microdialysis. J Neurol Neurosurg Psychiatry 59 326-327 Karcz-Kubicha M, Jessa M, Nazar M, et al (1997) Anxiolytic activity of glycine-B antagonists and partial agonists—no relation to intrinsic activity in the patch clamp. Neuropharmacology 36 1355-1367... 

Buspirone is a nonbenzodiazepine anxiolytic serotonin 5-HTia partial agonist that may have a role in reducing anxiety, flashbacks, and insomnia (Wells et al., 1991), although no controlled studies of this agent have been published in childhood populations. 

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. 

Several partial agonists are currently in development. Some are described in this section, others are described in the sections on subtype-selective drugs and the cyclopyrrolones. The work so far has tended to show the hoped-for features of lack of adverse effects, lack of interaction with alcohol, and reduced liability to cause tolerance, in addition to being effective anxiolytics. 

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... 

Stephens DN, Turski L, Jones GH, et al Abecarnil a novel anxiolytic with mixed full agonist/partial agonist properties in animal models of anxiety and sedation, in Anxiolytic Beta-Carbohnes From Molecular Biology to the Chnic. Edited by Stephens DN. Berlin, Springer-Verlag, 1993, p 79... 

Buspirone has selective anxiolytic effects, and its pharmacologic characteristics are different from those of other drugs described in this chapter. Buspirone relieves anxiety without causing marked sedative, hypnotic, or euphoric effects. Unlike benzodiazepines, the drug has no anticonvulsant or muscle relaxant properties. Buspirone does not interact directly with GABAergic systems. It may exert its anxiolytic effects by acting as a partial agonist at brain 5-HTia receptors, but it also has affinity for brain dopamine D2 receptors. Buspirone-treated patients show no... 

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