Metabolism and disposition of the dopaminergic agonist 5-hydroxy-6-methyl-2-di-n-propylaminotetralin in the rat.

As part of a program to investigate the metabolism and disposition of putative dopamine receptor agonists, DK-118 (5-hydroxy-6-methyl-2-di-n-propylaminotetralin) was chosen for study in the rat. Following a 3.85 mg/kg (ip) dose of 5-hydroxy[6-14C]methyl-2-di-n-propylaminotetralin, an average (+/- SD) of 100.3 +/- 12.2% was recovered in 67 hr: 77.2 +/- 7.9% in urine and 23.1 +/- 6.2% in feces. No excretion of 14CO2 was observed. In bile duct-cannulated animals, an average of 31.6% of the dose was recovered in the bile within 6 hr. After injection of bile containing radiolabeled drug/metabolites into the lumen of the duodenum, 30.2 +/- 1.7% of the injected radioactivity was recovered in the urine, suggesting enterohepatic circulation of some of the drug/metabolites excreted in bile. Highest concentrations of tissue radioactivity, 0.5 hr after ip injection of 14C-DK-118, were found in lung, kidney, and liver. Only a small amount of unchanged DK-118 is excreted into urine and bile; HPLC radiochromatography separated five metabolites in urine and at least eight metabolites in bile. The three major metabolites in urine (70% of urinary radioactivity) have been identified as 5-hydroxy-6-carboxy-2-di-n-propylaminotetralin, 5-hydroxy-6-carboxy-2-n-propylaminotetralin, and 5-hydroxy-6-methyl-2-n-propylaminotetralin-O-sulfate. The two major biliary metabolites have been identified as 5-hydroxy-6-carboxy-2-n-propylaminotetralin and an acid-labile conjugate of DK-118. Together, these data indicate that DK-118 is metabolized in the rat by a combination of N-dealkylation, oxidation of the 6-methyl carbon, and conjugation with sulfate.

Effects of metyrapone on the pharmacological activity, plasma levels and urinary excretion of the dopamine receptor agonist DK-118.

Possible metabolic activation of the dopamine receptor agonist DK-118 (5-hydroxy-6-methyl-N,N-di-n-propyl-2-aminotetralin) was investigated in cats. Metyrapone, an inhibitor of oxidative drug metabolism, was given to cats before DK-118 and the pharmacologic effects of the dopamine agonist were compared to those observed in nonpretreated animals. A sensitive high-performance liquid chromatography assay using electrochemical detection was developed to monitor urine and plasma concentrations of DK-118 in metyrapone-pretreated and control animals. The DK-118-mediated inhibition of cardioaccelerator nerve stimulation-induced tachycardia was reduced markedly in cats pretreated with metyrapone but the pretreatment had no effect on the hypotension or bradycardia produced by DK-118. In a separate group of cats, the tachycardia inhibitory effect of a nonbioactivated dopamine agonist, dipropyldopamine, was unaffected by metyrapone pretreatment, confirming that the inhibitor of drug metabolism does not interfere with this dopamine receptor-mediated effect. Pretreatment with metyrapone before a 0.14-mumol/kg i.v. dose of DK-118 increased the half-life, reduced total drug clearance and increased urinary excretion of unchanged DK-118. All of the changes are consistent with a metyrapone-related inhibition of DK-118 metabolism. The results of this study show that inhibition of DK-118 metabolism reduces certain of its pharmacologic actions, indicating that one or more of the metabolites of the drug may contribute to its effects.

Possible biologically active metabolites of 5-hydroxy-6-methyl-2-di-n-propylaminotetralin.

5-Hydroxy-6-methyl-2-di-n- propylaminotetralin 1b exhibits prominent peripheral presynaptic and central dopaminergic effects, and pharmacological test data suggest that this compound is metabolically activated in vivo. It was speculated that the 6-methyl group is oxidized. To evaluate this possibility and as a prelude to a metabolism study, 5-hydroxy-6-formyl 5 and 5-hydroxy-6-hydroxymethyl-2-di-n- propylaminotetralin 2b were synthesized. Both compounds exhibited marked potency/activity in a cat cardioaccelerator nerve preparation. The biological data on these compounds are consistent with the possibility of their being pharmacologically active metabolites of compound 1b.

Dopamine receptor stimulating activity of 5-hydroxy-6-methyl-2-aminotetralin derivatives.

The effects of 5-hydroxy-6-methyl-2-aminotetralins were evaluated for central and presynaptic peripheral dopaminergic activity. Di-ethyl (DK-121) and di-propyl (DK-118) derivatives inhibited the tachycardia produced by postganglionic cardioaccelerator nerve stimulation in the cat. This effect was blocked by haloperidol (100 micrograms/kg). DK-118 inhibited stimulation-induced contraction of the cat nictitating membrane. The pressor response produced by lumbar sympathetic chain stimulation in the isolated hindlimb of the cat was inhibited by DK-118 following intravenous administration. Reflex sympathetic activation produced by 30 sec bilateral carotid occlusion was also inhibited by DK-118 in the dog. Centrally, DK-118 caused contralateral circling behavior in rats who had unilateral lesions of the caudate nucleus. DK-118 did not effect DOPA levels in either the caudate nucleus or olfactory tubercle. In contrast, DK-121 decreased DOPA levels in the caudate nucleus but did not produce circling behavior in rats. Both compounds have weak emetic activity in dogs. These results suggest that DK-121 and DK-118 possess stimulant properties on dopaminergic receptors in the central and peripheral nervous system. However, DK-121 does not appear to stimulate postsynaptic dopamine receptors in the central nervous system.

Derivatives of 5-hydroxy-6-methyl-2-aminotetralin.

The title compounds were designed to provide semirigid congeners of m-tyramine in which the ring position ortho to the phenolic OH is blocked to metabolic hydroxylation. A sequence leading to a key synthetic intermediate, 5-methoxy-6-methyl-2-tetralone, has been developed. In animal test models for dopamine-like effects, the title compounds demonstrated qualitative and quantitative differences from the isomeric 5-methyl-6-hydroxy-2-aminotetralins and from 5,6-dihydroxy-2-aminotetralins. Two of the compounds were potent in a cat cardioaccelerator nerve assay, which involves dopamine receptors.