Cyclic nucleotides and the nervous system

Acknowtedgements This

rcvicw is hased IIn research span-

sorcd hy the Offtcc if Health and Envuonmental Energy.

Rcscarch, u&r

U S.

contract

Department

01

W-740~cng-26

with the Union Carbide Cqmration. P.J.H.

i.. a Postdoctoral

Inveqamr

supported hy subcontract No. 3322 from the Btology Division of Oak Rldpc National L;rbnrator) 10 the Urnvcr\iry of Tennessee.

Goals of chelate therapy A therapeutic chelating agent may be defined as a chelating agent which i$ given orally, i.v. or i.m. with the goal of corn plexinp it with a toxic metal ion and facilitating its excretion, generally in the urine and more rarely in the feces’ 2.‘u. The administration to the patient immcdialely faces us with one of the main charac&srics desirable in such compounds: a very IOU inherent level OCtoxicity of both the corn-pound itself ctnd its metal complexes. II also forces us lo acknowledge certain psychological desiderata: an orally administered drug is much preferred 10 one which must be given by injection. Chelaing agents have been successfully used in the treatmenl of metal poisoning for just under 4 decades. The introduction of 2.3 dimercapt~pmpanol- I (BAL. VU) as B chelating agent effective in the treatment of

arsrmc pusoning in the 194th mitiated the more systematic exploltatiam gri chrlatq agent* in the clinical treatment 4 rnc1.d poisoning ah well as Iah>rator) \tudls\ designed to elucidate theu mode 01 acltk:n. Since then many new chrlatmg .ipcnts hakr been prepared bul onlv a ven fcu hate merited consideration for deGlcd animal studies let alone clinical urge At tht\ prmt it is advantage~\us10 Iis1 rhr propcrtie\ that a chelating agtmt should have if it IL 11’ be pivcn scriou\ considcr.Mon hrr
I A low inherent toxtcit!, 2. Forms very htablc completes

\\Ith

toxic metal ions. Such complexr!. rrl.rc~ should have a low inherent toticiry 3. Water soluble and chemuall) arable 4. Undergoes a minimum of melahohc change in hdy 5. Can be administered orall)

336 that they have occur on an emer&ency basis and then: is not time to obtain thein. Finally, the economic burden of providing the testing necessaryto gel a drug approved for use 10 replace a marginally satisfactory drug (such as are the presently available and approved therapeutic chelating agents) has pFzvemed their use with humans in all but a very few research oriented clinics. Because the market for therapeutic chelating agents is so small. severalclinically usedtherapeuticchelating agentsare also used for quite different purposes. and it is these other applications which have carried the costs of their introduction Because any chelating agent which can bind zinc(ll). for example, will be found to be teratogenicif given at a high enough level 10 pregnant rats, the commonly usedtestsfor safetycan often be misleading. In the case of those chelating agenls used fijr the treatment of hereditaty disorders. such as Wilson’s disease (exces sive copper storage) or Cooley’s anemia (excessive iron storage). the situation is quite different and not analogous 10 the emergency treatment of acute metal intoxi cations. The developmentof new chelating agents for copper and iron has moved in a more systematic fashion because of the availability of human subjectson a regular basis.

The ‘ideal’ therapeutic chelating agent development model may lo seen in the development of D-Fnicillamine (1) fnr the treatment of the copper storage disease hepatolenticulardegeneration(or Wilson’s Disease)3.9. There the observation of an enhancedcopper excretion under the influ-

H,N(CH,),N-C(CH,),CNH(CH,).N-C(CH~)~CNH(CH~.)~~~-CCH~ In HO0

II 0

III HO0

II 0

II This compoundis’selective’ for Fc3’ and is produced by ,Frr~~onryces pifosus to extract iron necessaryfor its growth from the environment4. It has found use with iron-accumulationdisorders, espcciully in patientswith Cooley’s anemin who receive regular blood transfusionsover periods of years. Until the clinical induction of this compound, there was no effective wuy of preventingan ultimately fatal iron accumb lation in these individuals. By the UL: of injections or i.v. administration of this compound it is possible to bring such patientsinto a stateof negative iron balance in which the amount of iron excreted in the urine (as its U complex) is enhanced enormously.When given concwently with ascorbic acid, the amount of iron which is excreted is very significantly enhanced, but this must be done with great caic, as the too rapid mobilization of large amountsof iron in this mannercan be fatal. The fact that the compoundcannot bc given orally is a significant disadvantagein controlling the dis. order in young patients. and has led to a keen appreciation of the advantages of a selective chelating agent for iron which could be administeredor&y. R-C-N-R

II I

OH-O III

dihydroxybenzoic acid (V) and pyridoxal isonicotinoyl hydrazone (VI). COOH

0 -C---NH

VI V increasesthe urinary and fecal excrenon of iron but has relatively little etTecton the excretion of other essentialmetal ions. The clinical use of V was a disappointment’, even though it could be administered orally. In humans. a dosageof 25 mg kg-’ four times a day orally for a year resulted in no obvious retardation of the rate of accumulation of iron in the liver. VI is one 01 a series of closely related struclures which mobilize iron from the liver and the spleen and enhance both the urinary and fecal excretion of ion”. CH,-CH-CHP

I

I

I.

VU

I

&c-c---ct~---~

1’

CH2-CH-CKSOINa AH AH VU1

OH

0

IV The search tar new chelating agents for iron during the lustdecadehas resultedin an SubsequentlyWalshe demonstratedthat the extensive synthetic program for the prepaoral administrationof this compound leads rationof suchcompounds.This hasconcento a state in which there is a net excretion of trated on &late structures that contain copper from such individu&. He also bydroxamic acid groups (111) and the demonstrated that such indi*riduals. on a calechol (orlho diphenol IV) structure, regular regime of I, could lead al leas? groups found in the highly 5elective corn partly ‘normal’ lives. poundssynthesizedby micro.orgunismsto extract iron from their environment. The mch foli specificity: enhancing the Wliin severalof thesegroupsare present excretion of iron in a single molecule, such as II. the resulThe only therapeutic chelating agent in lam iron complex is very stable and is readregular clinical use which is a highly selec- ily excreted in the urine. nve chelator of a singlleion is desferrioxTwo compoundswhich can be adminisamine (DFOA, ii) tered orally deserve mention here, 2.X I

I

SH SH OH

ence of penicillin was traced to the action of

CM

--N=CH

Dithiols During the last decade or so it has become recognized that vicinal dithiols other than (VII) can be superior to it as antidotes. Many compounds of this type were first made by L. N. Owens. Of these, two compounds are of special interest, 2.3 - dimcrcaptopropane - I - sulfonatc (DMPS. VUI. synthesized independently by PctrunkitP. and developed extensively by Soviet investigatorsand called Unithiol b: ‘hem) and 2,3-dimcrcaptosuccinic acid (G. IS. IX].

HOOCCHl

CH,CDOti \ ,NCHzCH>-N-CHCH.-N”

HOOCCH, *’

~HLOOti

~CHtCOOH

x Roth of these latter compounds may he arlministcredotally. bothare water ~hthlc. tnrh have a much lower inheretn toxicity Ihan VII and h>Q have the ahihty to react with the same group of toxic heavy metal ions that VII does. In almost every respect they are superior tfl VU as heavy melal antidotes for species such as He*‘. PtP’ , As%’ . CtlrHg' . Cu(ll) and Sb(Ill). Their lower toxicity allows (hem (0 be administered in much larger amoums Ihan VII; this allows, in rum. a more complele reaction with the toxic metal and a more rapid transformationof it into the less toxic complex of the metal with the antidote. VIII has essentially no lipid solubility and is apparentlyconfined to the extracellular fluids subsequentto injection or absorp tion. In this respectis is quite different from VU which can penetrate the ‘blood-brain’ barrier. It is cleared from the body quite rapidly, via the kidneys and the urine, as arc the metal complexes which il forms. It is a compoundcapableof forming rather stable, water-soluble complexes with most of the metal ions which fotm insoluble sulfides, so ic does not possessspecificity towards the toxic metals alone. This doesnor interfere with its use as an antidote as the amounts of essential lrace elements e:,cretedconcurrently are quite modestand soonmade up by enhancedabsorptionfrom the diet. For mostof the essentialtrace metals, the body storesare distributed in a variety of forms fmm which they can be mobilized to make up any differences causedby a ternporn? lossof that species. IX is similar to VIII with respect to it: modest toxicity, pattern of reactions with metal inns and rapid clearance from the body. It does possess,however, some rbil-

Ily to p:netrate cell mcmhranc* and I* able ton~mow methyhncrcury from rhc hram’ There are very feu cast%m which Ihr\ corn pound cannot replace VII to ad\antrgs.

Trransurpaiumclements The work on plutomum decorpnr.t~n over the last 20 years ha\ led tn the uw of the ZaDTPA ~Dtethylenctnammcpmtaacetic acid DTPA. Xl complex for thr$ purpose. The complex of X uith zinc. suggestedh) Catsch“‘, i> reatimably stable and its ~,p. admimstratrnndoesnor deplete serum caC cium levels. It is also stgntficantlylessIOXIC than the calcium complex of X. The zinc complex retiily exchangesrrith plutomum to form thr plutonium complex and zinc. with the plutonium complex then heing rapidly excreted in the urine. Unfortunately. aged deposits of plutonium m the human body are much more difficult to remove, so that it is essential that &elate therapy be started as soon as possible after contamination. The similarities between the C(F ordination preferences of iron(M) and plutonium are quite marked. Thcsc have been usedas a basisfor the developmentfor new therapeutic cMating agent5 for plutonium which are far more selective in ther action than the ZnX complex. The* are catechol derivauves. similar to corn poundsof the sorts found naturally, and are effective in removing plutomum from rodents’. Other chelating agents u hich are cl&rwise highly selective for iron(llll cm alw be uwd to accelerate the excrrtm d plutonium. for example. II.