Antipsychotic agents approaches

Examples abound regarding the role of serendipity in the discovery of new therapeutic approaches, which on closer examination usually turned out to be the result of clinicians paying attention to unexpected clinical effects rather than discounting them. For example, lithium was tried first for hypertension, chlorpro-mazine was initially developed as an anesthetic, and imipramine was originally regarded as an antihistamine and an antipsychotic agent. Without astute clinical observations, these drugs would not have found their niche, nor would clozapine have been revived for the benefit of millions of the most difficult to treat schizophrenic patients. Other examples include the expanded indications of newer... 

Despite the advent of the atypical antipsychotic agents, efforts continue to identify other adjunctive medications that may improve response to standard treatments. In this context, we note that there is no consistent evidence that BZD monotherapy benefits schizophrenia. Another strategy, however, is the addition of BZDs to an antipsychotic regimen. This pharmacological approach is partially based on the evidence that GABA, which is facilitated by BZDs, inhibits certain dopamine tracts and that these medications may attenuate the dopamine system via a different route ( 339, 340, 341 and 342). 

A number of the major pharmaceutical companies have used biocatalytic approaches based on esterases and lipases to prepare target drugs or intermediates.107 183 187 Most of these approaches involve resolutions that use a racemic ester or amide as substrate, whereby yields of 50% can only be realized. Examples of resolutions applied to pharmaceutical intermediates such as the paclitaxel (Taxol ) sidechain and J -(+)-BMY-14802, an antipsychotic agent, have been described by the Bristol-Myers Squibb group.107... 

Trlcklebank. M.D. et al. (1992) Alternative approaches to the discovery of novel antipsychotic agents. Prog. Drug Res.. 38, 299-336. 

Schaus, J.M. and Bymaster, F.P. (1998) Dopaminergic approaches to antipsychotic agents. In Robertson, D.W. (Ed) Annual reports in medicinal chemistry. Acadamic Press, San Diego, 1-10. 

DBN (28) is an inhibitor of indoleamine-N-methyltransferase and effectively blocks the synthesis of N,N -dimethyltryptamine (DMT) in vitro and in vivo.40 DMT has been considered as an endogenous psychotogenic agent.4"1 Therefore, based on a rationa approach to drug therapy, compound 28 may be an antipsychotic agent. 

Schaus JM, Bymaster FP (1998) Dopaminergic approaches to antipsychotic agents. Aimu Rep Med Chem 33 1... 

Whereas iithium has been the standard approach, increased complications in elderly patients, especially when there is compromise of the CNS, endocrine, or renal systems, makes this agent a less attractive choice. Lower doses (e.g., 150 to 300 mg) should be initiated, with many elderly patients achieving adequate response on total daily doses of lithium in the 450- to 600-mg range. If a more rapid response is necessary, low-dose high-potency antipsychotics can also be used in the early phases. Alternatively, a BZD, such as clonazepam or lorazepam, may be indicated (297). 

Dopamine "Da-Plus Agents. As noted in Section 8, all antipsychotics except amisul-piride interact with a wide array of receptors. The potent Dg antagonism of all antipsychotics including amisulpiride has kept open the exploration of novel D2 antagonists that bind to other receptors, such as adrenergic or serotonergic receptors. This constitutes the D2 plus" approach for novel, atypical antipsychotics. 

---