Azapirones

A therapeutic alternative for treatment of anxiety and depression is the use of 5-HT1A agonists. Azapirones comprise the major class of 5-HT1A agonists of which buspirone (Buspar [4]) is the only FDA-approved 5-HT1A selective agonist (relative to the other 13 serotonin receptor subtypes) for anxiety currently on the US market (Scheme 19.1). Buspirone has shown efficacy in randomized controlled trials of GAD for which it was approved [5-7]. Unlike benzodiazepines, buspirone is not addictive... 

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... 

Eison AS. (1990). Azapirones history of development. J Clin Psychopharmacol. 10(3) SuppI 2S-5S. 

Azapirones. Though several azapirones have been developed and tested in the laboratory setting, only one, bnspirone (Bnspar), is currently on the market. Buspirone is the first nonsedating, nonbenzodiazepine anxiolytic, other than the antidepressants described earlier. It has no dependence or addictive liability and is not lethal in overdose. Buspirone is also devoid of many of the problems of the benzodiazepines such as sedation, motor impairment, addiction, physical dependence, or withdrawal. Yet, doubts remain in the minds of many practitioners regarding the effectiveness of buspirone. This will be discussed in more detail later in this chapter. 

Buspirone (Buspar). The azapirone, buspirone, has been tested in the treatment of panic disorder and found to be ineffective. 

All azapirones increase the turnover of both cerebral dopamine and norepinephrin. At high doses they cause a mild elevation of prolactin (Baldessarini, 1996). However, in humans, doses of 30 mg/day for 28 days led to no changes in the levels of prolactin, growth hormone, or cortisol (Jann, 1988)... 

Keppel Hesselink JM Promising anxiolytics Anew class of drugs the azapirones, in Serotonin 1A Receptors in Depression and Anxiety. Edited by Stahl SM, Gastpar M, Keppel Hesselink JM, et al. New York, Raven, 1992, p 171... 

It belongs to azapirones which is chemically and pharmacologically distinct class. It acts as a partial agonist at serotonin and dopamine receptors and having no hypnotic and sedative action. It does not interact with benzodiazepine receptor or modify GABA-ergic transmission. 

Eison MS. Azapirones mechanism of action in anxiety and depression. Drug Ther 1990 Aug[Suppl] 3-8. 

Buspirone is an azapirone anxiolytic that acts as a partial 5-HT agonist. In contrast to the BZDs, this agent has no immediate effect on the anxiety seen in patients undergoing medical procedures (e.g., endoscopy, cardioversion). Further, it cannot be given parenterally, because the drug is not available in an i.v. or i.m. formulation. Buspirone does not produce disinhibition euphoria and even in high doses has not been found to have antipsychotic activity. 

Scheme 70 Synthesis of 6-hydroxybuspirone 246 via the hydroxylation of the azapirone psychotropic agent buspirone (248).

Benzodiazepine and azapirone derivatives are widely used drugs in this class, and most are metabolized extensively by enzymes of the CYP3A family, except oxazepam, lorazepam, and temazepam, which are mostly glucuronidated (52). Again, several studies have shown that inducers and inhibitors of CYP3A can markedly alter plasma concentrations of many of these drugs, but in only a few cases have toxic effects, such as deep unconsciousness, been reported (19,52,53). Nonetheless, patients on these drugs should probably be monitored carefully, particularly the elderly, who may suffer severe physical injury as a result of falls from impairment of psychomotor function. 

Steinberg JR. Anxiety in elderly patients. A comparison of azapirones and benzodiazepines. Drugs Aging 1994 5(5) 335-45. 

Anxiolytic (azapirone serotonin 1A partial agonist serotonin stabilizer)... 

A new controlled-release azapirone related to buspirone is in late clinical testing as an antidepressant (gepirone ER)... 

Buspirone. The dominance enjoyed by the benzodiazepines is illustrated by the fact that no new anxiolytics were launched until buspirone (9)reached the market in 1986. Buspirone is a member of the azapirone class, and produces its therapeutic effects through partial agonism at 5HT-1A receptors. Buspirone is indicated and widely used for GAD, but has failed to show significant efficacy in other anxiety disorders (52). Although perhaps less consistently effective than the BZs, buspi-rone s improved safety profile provides the main point of differentiation between the two therapies. Buspirone causes less sedation, motor and cognitive impairment, and does not appear to be associated with any withdrawal syndrome. Drawbacks include a delayed onset of action (several weeks), and a reduced effect... 

Azapirones. Numerous SAR studies have shown that the N-1 aryl substituent plays a key role in determining affinity and selectivity for the 5HT-1A receptor, both... 

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