Biochemical and pharmacological studies on dopamine receptors

Watling, Keith James (1978) Biochemical and pharmacological studies on dopamine receptors. University of Southampton, Doctoral Thesis.

Abstract

A study has been made of dopamine receptors in rat brain using the dopamine-sensitive adenylate cyclase system, with particular attention being paid to dopamine receptors in the nucleus accumbena. The only active phenylethylamine derivatives in homogenates of this brain region were those containing hydroxy groups at the 3 and 4 positions on the benzene ring, a two carbon-side chain and a terminal nitrogen, either unaubstituted or containing a single methyl group. The a- and 3-adrenergic agonists, phenylephrine and isoprenaline respectively, were both inactive.The typical neuroleptic drugs, fluphenazine and a-flupenthixol,were both potent antagonists of the dopamine response as opposed to the atypical neuroleptics metoclopramide and sulpiride, and the sand f-adrenergic blocking agents, phentolamine and propranolol respectively, which were all inactive. The inability of sulpiride, a drug known to behave as a potent dopamine antagonist in certain behavioural systems, to inhibit dopamine-stimulated adenylate cyclase activity in slices of rat corpus striatum, adds further support to the hypothesis that some dopamine receptors in the brain may not be coupled to adenylate cyclase. Several 2-amino-1,2,3,4-tetrahydronaphthalene derivatives were also examined for their ability to both stimulate dopamine-sensitive adenylate cyclase in homogenates of rat striatum and nucleus accumbens, and to induce locomotor activity following their bilateral injection into the nucleus accumbens of rats. The most active compound at stimulating adenylate cyclase from both brain regions was 2-amino-6,7dihydroxy-l,2,3,4-tetrahydronaphthalene (ADTN), this compound being equipotent or more potent than dopamine. A series of N-alkylated 2-amino-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene derivatives also stimulated adenylate cyclase activity in these brain areas with the 2-dipropylamino derivative being almost equipotent with dopamine. These data, together with results obtained with other rigid analogues, including apomorphine and norsalsolinol, are discussed in terms of the preferred conformation of dopamine at its receptor site. The ability of a hypothetical metabolite of the drug nomifensine, 3',4'-dihydroxy-nomifensine, to stimulate adenylate cyclase activity in the above two brain regions emphasises not only the necessity for the 3,4-dihydroxy moiety, but also suggests that some of the dopaminergic effects of nomifensine could be mediated via this derivative. The similar results obtained with various 2-amino-1,2,3,4-tetrahydronaphthalene, nomifensine, ergot alkaloid and phenylethylamine derivatives together with antagonist data, suggests that the dopamine receptors coupled to adenylate cyclase in the rat nucleus accumbens and corpus striatum possess similar structure-activity requirements. Studies on the tissue distribution, metabolism and elimination of,j3H)-ADTN in the rat indicate that little ADTN crossed the blood rain barrier and the compound underwent rapid metabolism and excretion.

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