Agonist development, problems

From these studies it is clear that the progression of PAR-based therapy relies upon the future development of new specific agonists and antagonists for PARs 2-4 with much higher potencies than those currently available, with an efficient mode of delivery to target sites. However despite these problems the PARs still rqiresent one of the most attractive therapeutic targets for a number of disease states. 

Importantly, they achieve this without inducing extrapyramidal side-effects or increasing prolactin secretion, which are real problems with neuroleptics. These results have been borne out by preliminary clinical trials of buspirone, used in combination with neuroleptics, and several novel S-HTja agonists (e.g. BSF 190555) are currently under development for this clinical application (Meltzer 1999). 

There is less risk of developing motor complications from monotherapy with dopamine agonists than from L-dopa. Because younger patients are more likely to develop motor fluctuations, dopamine agonists are preferred in this population. Older patients are more likely to experience psychosis from dopamine agonists therefore, carbidopa/L-dopa may be the best initial medication in elderly patients, particularly if cognitive problems or dementia is present. 

Changes have also been reported to occur in the sub-unit composition of the GABA-A receptor following chronic exposure to barbiturates, neurosteroids, ethanol and benzodiazepine agonists. These changes may underlie the development of tolerance, physical dependence and the problems which are associated with the abrupt withdrawal of such drugs. 

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. 

---