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In order to elucidate the pharmacological properties of a series of 1-phenyl-2-aminopropane and 2-amino-1, 2, 3, 4-tetrahydronaphthalene derivatives, their ability to inhibit a number of apomorphine-induced behaviors was investigated. Several members of the series under study were potent inhibitors of apomorphine-induced pecking behavior in pigeons, emesis in dogs, and gnawing in rats. In addition, these compounds were able to inhibit responding in self-stimulating rats and to a lesser degree counteracted the depression of the linguomandibular reflex induced by 5, 6-dihydroxy-2-dimethylamino-1, 2, 3, 4-tetrahydronaphthalene (M-7) in the cat. The most effective member of the experimental compounds was N-methyl-5, 8-dimethoxy-2-amino-1, 2, 3, 4-tetrahydronaphthalene; however, neither this material nor any of the related structures were able to inhibit apomorphine-induced rotational behavior in substantia nigra lesioned rats. The possibility that the more effective members of the experimental series are able to inhibit certain apomorphine-induced behaviors by stimulation of central alpha adrenergic receptors is discussed.
In an effort to identify further the structural requirements for central dopamine receptor agonists, some monohydroxyl analogs of the known agonist 5,6-dihydroxy-2-dipropylamino-1,2,3,4-tetrahydronaphthalene were synthesized. They were examined for production of emesis in dogs and stereotyped behavior in rats. The most potent was 5-hydroxy-2-dipropylamino-1,2,3,4-tetrahydronaphthalene, which was more potent than apomorphine but less so than the dihydroxyl analog. The two enantiomers of the monohydroxyl analog were synthesized by conventional methods from an optically active intermediate, 2-benzylamino-5-methoxy-1,2,3,4-tetrahydronaphthalene. The resolution of this amine was performed with the aid of mandelic acid. Dopaminergic activity was found to be confined to the levo enantiomer. Requirements for both substitution and chirality in the tetralines were found to correspond closely to those known for the dopaminergic aporphines.
N-ethyl, N-n-propyl, N-n-butyl, N,N-di-n-propyl and N-n-propyl-N-n-butyl derivatives of 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (ADTN) were screened for dopamine vascular agonist activity. Effects of intraarterial injections of the drugs on renal and femoral blood flow were measured in pentobarbital-anesthetized dogs before and after phenoxybenzamine (POB), 5--10 mg/kg. All DDTN derivatives were more potent vasoconstrictors than dopamine (DA) before POB. The di-substituted analogs were approximately 1/4 and the mono-substituted derivatives were about 1/16 as active as norepinephrine as vasoconstrictors. After POB the two di-substituted analogs were about 1/4 as active as DA in causing renal vasodilation. The three mono-substituted analogs produced relatively minor and inconsistent effects on renal blood flow, and were more than 100 times less effective than DA as vasodilators. The two di-substituted analogs markedly increased blood pressure with little effect on cardiac contractility in doses up to 32 micrograms/kg; whereas, the threshold dose of DA is 4--8 micrograms/kg. This and our previous results show that structure activity relationships of DA and ADTN, a semi-rigid analog of DA, are similar. However, the rigid analogs tend to be more potent vasoconstrictors than their flexible chain homologs.
N,N-Disubstituted dopamine and 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN) analogues were synthesized and tested intraperitoneally in mice for dopamine agonism. Compounds inducing asymmetric postures in unilaterally caudectomized mice were further tested in mice treated with reserpine and alpha-methyl-p-tyrosine methyl ester. ED50 values determined for reversal of reserpine-induced catalepsy were used to rank drug potency and correlated with molecular structure. N-n-Propyl N-substituted compounds were more effective than other N,N-dialkyl homologues. Of these, analogues with one alkyl group larger than propyl became inactive or their dopaminomimetic effect was reduced when the propyl was replaced with a larger group. N-Monosubstituted analogues were inactive as dopamine agonists. N-n-P-r-N-n-Bu-6,7-ADTN was six times more potent than N-n-propyl-N-n-pentyl- and N-n-propyl-N-phenethyldopamine but ten times less potent than apomorphine. The availability of an array of structurally related dopamine analogues with dopaminomimetic properties may make it possible to test the hypothesis that there are more than one type of dopamine receptor and that stereotypy and locomotor activity may have different central nervous system loci. Moreover, they may be of potential use in the treatment of parkinsonism and other extrapyramidal disorders.
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The authors investigated the pharmacokinetics of the pressor substance 5,8-dimetoxy-trans-2-/2-hydroxyethyl/-amino-3-hydroxy-1,2,3,4-tetrahydronaphthaline hydrochloride (1b), which possessed strong pressor action. Blood concentrations after venous administration in a dose of 1 mg/kg of body weight were determined by means of exctration spectrofluorometric method. The data complied with the biexponential equation, meeting the requirements of an open two-compartment model. There was a quick elimination of the substance from the central compartment, which correlated also with the data for quick disappearances of the effect on the arterial pressure.
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