ADTN — a potent dopamine receptor agonist

ADTN - a potent dopamine receptor agonist

4tudy the dopanune receptor aponi\tr au,j anlagonists. o~OUS

and have mdde great L‘OR tributiom to this Beld. hut it 1s often dlf-

ticult to interpret khaviourdl

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~vascularand 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 it 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 (1)

data in term\

ofdirect. asopposed toindirect. actionsatr

Geoffrey N. Woodruff

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

~~ehavtoural \tudrec are of

QalUc

!?I

dopamme receptor. In recent jeitr5 there has been a big upsurge m intere*t in recep tm binding aswy+. both m the evaluation of dopamine receptor agonuts and antagos I\IS. Again. great care mu\t he taken m utterprcting the results of bmding assays. The data obtamed should. of po~blr. bc correlated with the known physiological respon*sof the *y$tem. EReetdADl’!U

on IWIJ~~IWS

One of the earliest m&la uuld for tnvec ligating the actions of dopaminc receptor agonists wa the iwlated btatn of the \ndrl. Hdis u.~perso’. A group of idenntiable ncurone~ in the brain of the *natI $*rehypcrpolarized and Inhibited by low coacentrations of dopaminc. The receptor\ mrd;armg this response arc true dopamine recepton quite unbkc I(- or $-xlrencrgtc r~cptoThcrc is a high degree of specificity aud the structural requirements for dopamme-lihe activity on the cells is very precise1 1 The response to doparnine on theu cells 13 blocked by the ergot alkaloids ergometrine and LSD’ and also by the atypical neurolcp tic sulpinde’. XDn has a potent dopamine-likr actton on rbcx neuronc’i. .USlX is approGmately rquip~rnt urth dopamine and bovcr 101)tune\ more active than 2 - amino - 5.6 - dthydro\y - 12.2.~retrdhydronaphthalcnc: m thih respccr’ Also. the R-( - )_cnanuomer of .U)TS IL ahwt a hundred time\ more active than S( - t-.-u)T?i. .A ~tmrlar order of PWnsy of ADTX and thr S.r%drhydroxy dctivame has been found on snothcr group oi neurones on the snail brain in u hich dopamine has an e\citaton cffecr‘ Much of the informauon available concerning drug\ on m.unm.rlt~n ccntr~l dopamine receptors has come from stud~zs ustng biocbemisal tcchniqurz Ho*c\rr.

the drug is injecmd info the I;rferal venfricauses a potent and longlastingrotationaway from the lesionedside indicating a direct action of the drug on posI-synaptic dopamine recepcOn. AS in other tests, R-f+l-ADTN is mom active than S-( - ).ADTN in this test”. clcs. ADTN

hy metaciopromide. ADTN

is a FenI agonist at these prcsynapnc dopiimire mcepIorxand is mom potent in this mspect than 3amino-S. 6 dihydmxy - 1,2.3.4tetralIydronaphthaleners.

otttereRecbtofADTN ADTN hasother actionsin additionto us effects on dopamine rcccptoh. For cxa npie. the drug i\ a poacrful agonisI on ttrz The first evidence to be pmduced sugi.solatt%l rat anococcygeusmuscle.although gestingthat ADTN actsondo~rni~ recep its potency is much r&c&. relative Io 101%in the periphery came from studieson noradrenaline. after pm-treatment with the anaesthetized guinea-pig blood pres 6hydroxydopamine. This and orherresu$s sum. We showed that ADTN. like suggestthat ADTN has a weak action on dopamine, causesa doserelated depression post-synapticcr-recelnofsand can additionof the blood pmssumin this pmparation”‘. ally causethe releaw of noradrenalineafter The by~~sive action of ADTl+l was first being taken up into neuroneson tw thoughtIO be unlikely to be due to an effect pmsynaptic noradrenaline uptake sites‘. on &mceptors since it was unaffected by ADTN can also be accumulated into talent with ~m~lol in doses which completely blockedthe depmssoreffects of brain. ADTN taken up into dopamine terisoprenaline.More recentlywe have shown minals can be subsequently released +ry that the akin an~~ist sulpiride is a potassiumdepolarization.Tbe stereo&em potent and specific antagonistof the deical requimmentsfor afRniIy of ADTN at pressormsponsesto ADTN or dopamineon dopamine upmke sites arc Iess stringent the guineapig blood pmssurP. Sulptide than whoseat dopamine receptors. Thus. does not however block tbe depressor I+ ).ADTN is only three to five times more effects of isopmnaline on Ibe guinea-pig potent than f- I-ADTN in inhibiting the blood pressure. Goldberg and hi coiuptake of tritiated dopamine into nerve terleagues have produced compelling evi- minals in homogenatesof rat sniatum”. dence that the renal vasodilatoraction of dopamine in the anaest~tiz~ dog is due conelusiomI to a specific effect on post-synaptic ADTN is one of the most potent dopamine mcep~ors’~. The snucture-activity dopamine mceptor agonists known. In ~ui~~n~ for d~i~~~e mnal vase dhect testsof dopamine mcepror function. dilatation am very precise and are strik- where it is possibleto meastuea physiologingly similar to the structuralrequirements ical responseto the agonist. ADTN has for activity on the sniatal dopamine been shown to be at least equi~tcnI urth sensitive adenylate cyclase. PDTN is dopamine and much mom active Ihan ~he equipotent with dopamine in producing S.(idihydmxy derivative. This rtmnply of renal va~iiatat~n in the dog whereasthe suggcts that the active c~~nf~?~aIi~~n Lbdihydmxy derivativeis compldely inrtc- dopamine. when it is acting at its recepr~r. river*. ADTN hasalsobeenshownto havea is in the fully extended form @-rotamerl. ~min~like relaxant effect in isolated In all casesexamined. tbe ( + ~en~tiomer arterial preparations.For example, the iso- is considerably more active than lated splenic branchof the coe!iac artery of (- )_ADTN although the difference in the &bit pretreated with p~noxy~nzpotenc>-of the two enanti~~me~is noI so amine and propanolol specifically relaxes great on dopamine upake sites. TritiaIrJ when treatedwith dopamine. This effect of ADTN hasbeen shownto be a useful&gv+ dopamine is blocked by the dopamine ist ligand in do~rn~~-~cept~~ bindtng studies. The UC of i + l- and (- LADTS receplor amagonist bulbocapnine. ADTN is more potent than dopamine in relaxing and of the S,tLderivative will also prove to be valuablein es.ablishingorders ~>fpot~% this ~p~ti~l~. II is known that some sympatheticnerve ties in binding studiesusing other ligdnds terminals contain pmsynaptic dopamine where it is noI possible to measure the mceptom. the ~ti~ti~ of which leads IO physiologic~ response. fn &se ~rudiexit inhibition of norddmnaline mlease. This should be posGblr, using thcx con& response can be measumd either as an pounds.to distinguishbinding to mcepron: in~bi~n of the end organ response to and binding to dopamine uptake &es. The sympatheticstimulationor as inhibition of potentbehaviouralactionsof ADTN am of value in studying the physiologrcalfuncrelease of titiated noradnmaline. The is6 tions of dopamine in lhe brain. In paniculated &bit ear artery responds to sym pathetic stimulation with vasoconstriction. tar. the ADTN hyperactivity test ts a useful This response is inhibited by dopamine. methodofevaluating newleptic-like activand the dopamine respunsecan be blocked ity. Although ADTNit~lf~s~t~t~