ADTN — a potent dopamine receptor agonist

Abstract

In tccent years then: has been considerable interest in the development of potent and selective dopamine receptor agonists. Drugs which stimulate post-synaptic dopamine receptors in the striatum have proved to be remarkably effective in the treatment of Parkinson’s disease. In addii tion to the post-synaptic dopamine recep tots, there is also evidence for the presence in the CNS of dopamine autoreceptors. either located on dopaminecontaining terminals (axon terminal autoreceptor) or located on the soma or dendrites of dopaminecontaining neurones. Drugs acting as selective agonists at dopamine auto receptors, either axon terminal or soma dendritic, would be expected to inhibit the release of dopamine. Such drugs might be of potential value as antLpsychotic drugs. In the pituitary. dopamine receptors appear to be involved in regulating the release of certain hormones, for example pmlactin secretion is inhibited by dopamme receptor agonists. Such drugs may therefore be useful in the treatment of certain endocrinological disorders such as hyperpmlactinaemia. Dopamine receptor agonists may also be of value for their peripheral catdio~vascular and renal actions, for example in the treatment of congestive heart failure and shock. The demonstration that there are present on sympathetic nerve terminals presynaptic dopamine receptors, the activation of which leads to inhibition of notadrenaline release, has led to the realization that peripherally acting dopamine receptor agonists might also be of value as antihypertensive drugs. Thus, there is considerable interest in the development of potent and selective dopamine receptor agonists. The present article is concerned with the actions of ADTN (2 amino 6.7 dihydmxy I .2.3.4 tetrdhydronaphthalener). one of the most potent knowa dopamine receptor agonists. The dopamine molecule is. a flexible structure which can adopt a number of different conformations. The kquinoline norsalsolinol and 6,7 and S,Sdihydmxy derivatives of 2-aminotetralin contain the dopamine skeleton in a fixed semi-rigid structure. These compounds have been used in an attempt to obtain informati ,n about the active conformation of dopaminc when is acting at it receptor’ z. Thus. norsalsolinol correspon& to the folded form of dopamine in which the phenol group iscir to the amino group. ADTN errresponds to an extended, rrons . confomra tion @-mtamer) whereas 2 amino 5.6 dihydroxy 1.2.3.4 tetrahydio naphthalene corresponds to the extended form (a-mtamer) (Pig. I ). The molecult of ADTN contains an asymetric carbon aerm and thusexhibits stereoisomerism. The two enantiomers have recently been resolved by Dr John McDermed and his colleagues’ aho have shown that (+ )_ADTN HBr has the R absolute contiguration. A number of methods are available for evaluating the activity of dopamine recep tor agonists. In a few cases, the tests are direct and consist of comparing the physiological response evoked by dopamine with that evoked by thr corn pound under test. Examples of tests in this category ate studies in which dopamine has been shown to act on receptors on inverts brate neumnes. on neurones in the nummalian CNS andh viva orin vitro studies on the peripheral vasculatulr. Care has to be taken, even in these socalled duect measurements. to ensure that the corn pound und::r study is not acting indirectly by releasing an endogenous substance cr by activating some other receptor system. Other less direct tests have also been used to