PHARMACOLOGY

Porin - biological diversity leads to many potential es

-Susan Grant-

Investigators from a variety of disciplines share a common thread to their research: the study of purines. This biologically diverse class is potentially useful in cardiovascular, neurological and endocrine diseases. The current state-of-play in each of these therapeutic areas was discussed at the 12th International Congress of Pharmacology [IUPHAR; Montreal, Canada; July 1994].

Early clinical attempts to use adenosine agonists in the treatment of hypertension were hindered by the occurrence of 'conduction block'. Despite this, researchers have persevered and there is now a vast array of adenosine modulators in trials for this. and other. cardiovascular indications [see table]. Furthermore. adenosine has been licensed for the treatment of supraventricular tachycardia associated with atrioventricular conduction disturbance.

In the heart, adenosine is generally a depressant. exerting this effect through its interaction with the G-protein-coupled AI- and A2a-receptors. In the vascular system, its major effect is dilation.

Exactly how adenosine is able to provide cardio­protection is still unclear. It may be involved in the phenomenon of preconditioning in which mild hypoxic stress protects the heart against subsequent prolonged ischaemia. although the mechanisms by which this is achieved are as yet unknown.

Potential in stroke? In the central nervous system, activity at the

abundant adenosine receptors appears to: • modulate neurotransmitter release both pre- and

postsynaptically • influence cerebral blood flow, and • protect against anoxia in in vitro experiments.

Therapy based on adenosine pharmacology holds promise for the management of stroke; however. direct-acting AI-receptor agonists produce a severe decrease in heart rate and blood pressure. both of which create problems for use in these patients.

On a brighter note, a beneficial effect on measured infarct volume in a rat model of transient cerebral artery obstruction suggests that adenosine modulation may afford some site- and event-specific protection. Thus, future use in prophylaxis against stroke during heart surgery may be a possibility.

Adenosine-based therapy may prove useful in a number of other CNS disorders. However, there are several confounding factors involved in the development of such drugs [see boxed text].

Confounding factors in the deftqMnmt of adeP&ne mcxhda1nrs for CNS dysIimdion

• Receptor subtype specificity is often obscured by overlap in pharmacological activity.

• Confusion often exists (especially in animal models) between direct neurological effects and those which are secondary to cardiovascular changes.

• Agonist and antagOnist activity at receptors frequently changes when administration is chronic.

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Table:

Adena.lne Indication St.ge of loIanuf1lctu r.ceptor drftlopment

KW-3902 Phase I Kyowa HaI<ko

MDL·l02S03 A" CogIItive Predll'lical Marlon antagonist c:Isordets Merrell Dow

KFM-19 A,· Cognitive PreclinIc:aJ Boehringer antagonist clsorders; Ingelhelm

Illedive cIsorders

MDl·102234 A" agonist CognftiYe Preclinical Marlon cIsorders Merr I Dow

1(F·17838 A" AIIacIive PradInIcaI Kyowa antagonist cboI'ders Hakko

M-218765 Antagonist AIIacIive ~ Zeneca cIIordeB

MDL·101483 ~ P$ychotic PTedinleal Marlon cIsorders Merrell Dow

UP-20232 Agcnst PaIn Prectncal UPSA

FK-453 A,- HypertsnsIcn; Phase II; F!4i antagonist heart ure pr9CllnicaJ

(respectively)

N..()861 A· Hypenenslon; PreclinIcaJ WhItby antagonist MI; stroke Phenna·

ceulicaJs

YT-I46 A.ragonisl HypertsnsIcn PhaMII Toe8yo

COS-24012 A.ragorjst HypertsnsIcn PreclinIcal ~ CGS-2168OC A2-agonIst HypertensIon DIscon nued ~ KS-341 Agcnst HypettensIon PrecIWIIcaI Sankyo

~ A antagonist Heart Un! PracllnIcaI WhItby Phenna-ceuIicaJs

Dralla2ine AntJlgOnlst l&c:haemla Phase II JatIIIMfl

AcadesIne AgonIst IIChaemIa P~IIonGeosia

SOZ-WAG- A,. ArrtlyItvnIas PrecIinicaJ Sandoz 994 antagorUt

P0-81723 A,-.goni AnhyItmIas No PaN-OavIa deYeIopmenI repor1Ied

CV-1 808 A.ragafUt ArrhyIhmIu; DiIcontInued Talceda IIdIaerrQ

GP-14683 AdenosIne IschaemIc PrecIncaJ f1IIII*!lng hMrtdseese agent

D-4398 AnIIIgonIs.1 PeI1phInI Prec*Q/ l.eneca vasc:&Mr Itso!de!s

GR-79236 A,-.goni 0IabNIs DIscontinued GIaxo ITllllltus

Some of the approaches suggested include chronic use of an agonist in sleep disorders. pain syndromes. and neurodegenerative diseases. In the latter indication. the AI-receptor agonists KFM-l9 and MDL-l02234 may act as cognition enhancers.

Chronic agonist administration in patients with epilepsy may help establish a high seizure threshold through tonic stimulation of endogenous anti-

19

PHARMACOLOGY

Purin - continued

convulsant mechanisms. In contrast. antagonists are proconvulsanL

Adenosine also acts as an indirect dopamine agonist and was shown to be neuroprotcctive in a model of Parkinson's disease. Aucntion deficit disorders and substance abuse are other therapeutic indications in which adenosine-based therapy may prove useful.

As reported by Dr D Hillaire-Buys from the University of Montpellier in France, there may be a role for purines in the management of diabetes mellitus. With regard to diabetic complications, adenosine may be useful due to its action on glucagon-secreting A cells of the pancreas, and its effect on vascular tissue.

Purine antagonists may also find clinical application in the management of renal failure. Dr A Karasawa of Kyowa Hlkko reported his results with the AI-adenosine antagonist KW-3902, now in phase I trials. This drug demonstrated a protective effect against the renal toxins glycerol, gentamicin, and cisplatin. KW-3902 has diuretic and natriuretic activity, and was effective in reducing oedema associated with renal failure without adversely affecting renal or systemic baemodynamics. -