Thiazoloindans and thiazolobenzopyrans: a novel class of orally active central dopamine (partial) agonists.

The 2-aminothiazole moiety has proven its value in medicinal chemistry as a stable and lipophilic bioisosteric replacement of a phenol group. This approach has provided dopamine (DA) agonists with good oral availability. To further explore its use in the development of DA agonists, we have combined the 2-aminothiazole moiety with 2-aminoindans and 3-aminobenzopyrans, which are known templates for DA agonists. In this study we have synthesized 6-amino-3-(N,N-di-n-propylamino)-3,4-dihydro-2H-thiazolo[5, 4-f]-[1]benzopyran (12) and 6-amino-2-(N, N-di-n-propylamino)thiazolo[4,5-f]indan (20) and several analogues (13, 17, and 21). The affinity of the thiazolobenzopyrans and thiazoloindans for DA receptors was evaluated, which revealed compound 20 to have high affinity for DA D(3) receptors. In addition, the compounds were screened for their potential to inhibit lipid peroxidation, to determine their radical scavenging properties. Compounds 12, 20, and 21 were subjected to further pharmacological evaluation in a functional assay to determine intrinsic activity. Compound 20 was also studied with microdialysis (to determine effects on DA turnover in striatum) and in unilaterally 6-OH-DA lesioned rats (to determine their potential as DA agonists). These studies selected compound 20 (GMC 1111) as particularly interesting. Compound 20 caused a rotation activation in unilaterally 6-OH-DA lesioned rats and an increase in DA turnover in rat striatum. This dual agonist/antagonist action is best accounted for by its partial agonism at striatal DA D(2) receptors. Interestingly, 20 displayed long-lasting activity and excellent oral availability in 6-OH-DA lesioned rats, making this compound potentially useful for the treatment of Parkinson's disease.

Time-dependent changes in hypothalamic dopamine metabolism during feeding in the rat.

The accumulation of the dopamine metabolite dihydroxyphenylacetic acid (DOPAC), but not the serotonin metabolite 5-hydroxyindoleacetic acid, in the hypothalamus is increased in rats during the second, third and fourth hours of a four hour period of access to food following a 20 hour period of food deprivation. This metabolic change does not correlate with duration of access to food or with amount of food consumed. These results suggest that increased hypothalamic dopamine metabolism during feeding is not related in any simple way to either the onset or termination of feeding.

Feeding increases dopamine metabolism in the rat brain.

Feeding induced by food deprivation is accompanied by an increased production of the dopamine metabolite 3,4-dihydroxyphenylacetic acid in the brains of rats. This neurochemical change occurs in the nucleus accumbens, the posterior hypothalamus, and the amygdala but not in other dopaminergic nerve terminal fields such as the corpus striatum. These results indicate that the release of dopamine from particular groups of central neurons is increased during feeding and suggest that anatomically distinct subgroups of central dopaminergic neurons serve different roles in the regulation of food intake.

Synthesis of catecholamines from [3H]tyrosine in brain during the performance of operant behavior.

Changes in the synthesis rates of dopamine (DA) and norepinephrine (NE) in brain were found to accompany the performance of positively reinforced operant behavior in rats. Catecholamine synthesis rates were estimated at short time intervals after the intraventricular injection of [3H]tyrosine with use of a conversion index which expressed the levels of [3H]DA or [3H]NE accumulated in various brain regions as a function of the specific activity of [3H]tyrosine. In rats lever pressing on a fixed ratio 5 schedule of water reinforcement, the DA conversion index in the caudate putamen was 66% higher than in control rats but was not different from control values in the mesolimbic area and hypothalamus. The NE conversion index in operant-performing animals was 48% higher in the hypothalamus than in controls but was unchanged in the mesolimbic area, telencephalon and brainstem. The changes in the CA conversion indices seen during operant performance were associated with increases in the brain levels of [3H]DA or [3H]NE, but were not accompanied by alterations in either the specific activity of [3H]tyrosine or the endogenous levels of catecholamines. The relative increment in the DA conversion index seen in the caudate putamen of operant-performing rats was directly proportional to the number of lever presses emitted following [3H]tyrosine administration. These findings indicate that the performance of operant behavior is associated with increases in rate of catecholamine synthesis within select populations of central neurons.