Schizophrenia affects about 1% of the population worldwide. 1 The onset of symptoms is generally in the late teens to early twenties. There is no cure for the disease, and current therapies have numerous, debilitating side effects. The combination of early onset of chronic disease and problematic therapies results in high costs for the patient, his or her family, and society at large. 2 While the etiology of schizophrenia remains unknown, several lines of research point to the dopaminergic system, 3 and, in particular, the dopamine D 4 receptor, as important in schizophrenia and psychotictype diseases in general. 4 Classical antipsychotics such as haloperidol, though effective in treating certain schizophrenic states, cause extrapyramidal side effects and tardive dyskinesias. These side effects have been linked to the blockade of dopamine receptors in the striatum. 5 Clozapine (1), an "atypical" antipsychotic, is relatively free of extrapyramidal side effects, but causes tachycardia (25%), sialorrhea (30%), dizziness (20%), drowsiness and sedation (40%), and agranulocytosis (1-3%). Many of these side effects can be attributed to clozapine's high affinity for a number of central nervous system (CNS) receptors. 6 At the same time, clozapine's affinity for the D 4 receptor may play a part in its atypical nature.
The racemic triflate derivatives 5-8 of the 5-, 6-, 7-, and 8-hydroxylated 2-(di-n-propylamino)-teralins 1-4 were shown to possess similar pharmacological profiles to their phenolic counterparts in in vitro binding and in vivo biochemical and behavioral assays in rats. Consequently, subcutaneous administration of the 5-, 6-, and 7-triflates displayed essentially dopaminergic agonist properties, while the 8-triflate was shown to be a selective 5-HT1A receptor agonist. With respect to their agonist activities, the triflates were less potent than their phenolic analogs. The absolute oral bioavailability of compound 8 (8-triflate) was 4-5 times greater than the corresponding hydroxylated compound. Interestingly, in the in vivo biochemical assay compound 8 was found to be more potent after oral than after subcutaneous administration, indicating formation of one or more active metabolites. Following a study of the metabolism of compound 8 in rat hepatocytes, the monopropyl analog 9 was identified as the major metabolite and was surprisingly found to be more potent than compound 8. Oral administration of compound 5 (5-triflate) resulted in behavioral and biochemical effects indicative of mixed DA/5-HT1A agonist properties not seen after subcutaneous administration. These results may also be indicative of the formation of active metabolites.
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