- Email: [email protected]
Strategy in drug research
TIPS -April
132
_I
Strategy in drugresearch The Second IUPAC-IUPHAR Symposium, Noordwijkerhout, The Netherlands. To make scientistsfrom diversediscplines tdk IO each other. you organize a sym r&urn with rather diverse presemations witbout parallel sessions.Workers in drug mesearchhave a wide scope of scientific criemation, which generally allow!, them F;* only to keep their job going but alsoto * njol; mostof the lectures presentedat a meeirnglike this. But you take Ihe risk that F.&Hsvtry QSAR-specialist understands ‘@-level presentations on n-receptor fiiocbmistry by Alexander Levitzky and Daphne Atlas., and certain biihmical phammzologistsfail to catch the essenceof a talk on the *lice of predictive calculat. ions by Yvonne Mattin. iiowever. such a symposiumreally createsa fertile environ ment for informal interdisciplin~.~ contacts. Only the neighboutingbulb farmer at one instantexaggeratedthe envimnmental fertility by spreadingexcessiveamoumsof chickendung to fosternext year’s be.rutyof the Dutch landscape.
heldfrom 25 IO 28 August 1981 in
problem. Mefioquine. tiiscovered by the Walter Reed Army Instituteof Re.seatch,is in an advancedstateof development;however. in laboratory situations. resistance can be. developed against this compound Ioo. A new lead is being worked out in collaboration with Chinese scientists. Quing Hao Su or arteannuin,a traditional remedy derived from the plant Artemisia unttuu, containsas the active principle a sesquiterpene lactone(Fig. I ) which is a novel compound in antimalarial therapy’. Chinese scientistsan: testingderivatives of this s-lure, which have shown to be more potentin rheir antimalarial action.
H. Mdhler (Hof&nann-La Roche) gave an overview of the presentthoughtsabut how benzodiazepineswork. In a nutshell, it is assumedthatthe benmdiazepinereceptor is localized in the postsynapticmembrane of the G ABA-trceptor. Here, it is pmbably involved in an allosteric interaction beTo start with. the medicinal chemist was tween the GABA-receptor and the chloride broughtdown to each by Dr Adatokunbo rhanncl. This enhances GABA-ergic 0. Lucas, director of the Special Pmgmm synaptic inhibition in the central nervous in Researchand Training on Tropical Dis system, and Ibe reinforcement of this easesof the WHO in Geneva. When; for physiclogical inhibitory mechanismshould example. an illness like malaria in certain be Ihe mis of the main centraleffectsof Ihe ateas is so persistentthat, even if 99% of benzodiazepines.Of course, much attentthe mosquitoesshould be killed, the in& ion WPSpaid to the recent findings of hen. dence of infection would be still 40 times zodiazepine antagonists(cf. Green rips in higher than‘ the minimal necessary for the issweof last AugustP).It was fascinating transmission,it isclearthat the roleoidmgs lo see in a shon movie the fast effect of is limited. For dealing with tropical dis these compoundsin abolishing the effects easesthe ideal drug shouldbe highly effec- of diazepam on mice, dogs and monkeys. tive, safe, simple to apply ;tnd cheap. More details aboutstructuresand activities Focusing on malaria, the emergence of of these antagonistswere presentedby W. strainsof Plarmodiutn fulciparum which Hunkeler and E. Kyburz ia a poster comate reshtantto 44ninoquinolines and other munication (Fig. 2). drugsin common use. is a mastchallenging A high structural specilicity is shown. Apparently, activity diffe=nces cannot be accounted for in terms of S and R COW figurationaroundthe %carbon in the seven. memberedring. Probably.the conformation of the seven-membeti ring plays a major role. In the discussionatter MBhlefs prs sentation, Ari&s suggestedthat, as these powerful benzodiazepine antagonists do notexert anyeffectsoftheirown. it isquestionable whether an ‘intrinsic’ hem diazcpine receptor ligand does exist. In Mohler’s opinion, we ate all somewhat
1982
brainwashed by the discovery of the endogenous opiate agonists. the endorphins. in this respect. There should be no DPMM (1 priori that an intrinsic receptor agonistexists. Cenainly. thisdebatewill be continued.as in the meantime the isolation otul characterizationof a protein from rat tivsrlewith benzodiazepinereceptoraffinity (‘nephentin’) is repned by people from Wellcome. U.S.A.s. More SLXwith Juacex? J. Knoll hnm Budapes had no problems in attractingattention with his story on the selective MAOB inhibitor (- )deprenyl (Jumexs). He put forward the hypothesis that, if the age-dependentappearance of
KS0 ~1000
!Cmjo’6,4
parkinsonian symptoms and ‘involutional depression’can be attributed IO a decnaie of dopamine (and perhaps other trace amines) in the bruin, other age+dependent symptoms like the decline in male sexual vigor might be a consequenceof the same biochemical event. (Was he peraaps also triggeredby the latter effect beink 3 notorious side effect in the LDDPA-therapy of parkinsonism?). Well, the selective MAaB inhibitor (-)iieprenyl exerts its action by increasing selectively the ‘brain levels of dopamine. So why not test tbis hypothesisby administering (-)deprenyi to old, male, sexually sluggishrats? And indeed, a highly signifEant increasein sexual activity, scored as the numberof intm missionsper minute and the appearanceof
TIPS -April
IV82
CH;I-$H-~)I-CH~-CECH CHg CH3 deprenyl
0 ’
’ CH2-CH-fj-CH2-CECH tH3 CH3 U-1424
ejaculations, was found. However. this attractive simple picture was complicated by the findings with compound U- 1424 (Fig. 3). This is a ‘pure’ MAO~inhibitot. devoid of either calecholamine releasing or motto amine uptake inhibiting effects. and its ineffectivity to give a similar increase in sexual activity suggested thal t - hleprenyl exerts its aphtodisiae effect probably by another mechanism (m-uptake inhibition?). Anyway. as the mean age of Knoll’s audiince was on the declining side of his mean sexual vigor curve. a vigorous di5 cussion was smrted. Further resulb are eagerly awaited.
Drugs: softor SIPble? Originally. it was not aimed to have in the session on ‘Toxicolopical Parameters as a lead a performance of both N. B&r. the promoter of the Soft Drug Approach. and the ‘hard drug’ advocate. E. J. Ariens. but as the planned contribution on N.nitrosamines by R. Preussmann was cancelled because of an unforttmate accident. the organizing committee was glad to find Ariens willing to substitute. So an interesting debate between two different concepts was offeted. Bodor stated that a predictable in Vito destruction to nontoxic moieties is to be preferred. One of the prim ary concepts is to avoid most oxidative metabolism - which mostly ~IXS thmugh highly reactive intermediates-but to use as much as possible dte hydrolytic mechan. isms. e.g. the various esterases. A simple
example is the replacement of the bacteria static cetylpyridinium chloride by an estercontaining analog (Fig. 41.
CH,(CH2),zCH?CH~CH2i;Jo 3
Cl-
CH3(CH$,Z-$-
CI-
0
0 -CH$j
A lot of endogenous substances tsteroid hormones. dopsmine) can be conbidercul as natural utft drups. uncc the huly has developed cffiient. fast and safe metabolic ways for tlir rcmovat. So if. for cxampte. a steroid hormntc can bc released at w-h a rate that tt can be coped with by the normal metabolhm of the body. you c.ut talk of a prodrug-soft drug combination. On tbe other hand. you can look at tbc ihicttve metabohtes and generate a precursor which resembles the active compound Taking hydrocottisotte for examp!e. some interecting examples were shown (Fip. S). After this presentation. Art&s also sue+sed the necessity of petting drug metabolism undercontml. However. he started from the viewpoint: ‘drug metabolism is dtug waste’ (Fig. 6). Non-metabolizable. highly active compounds have to be admuustcrcd in very small quantities only. making the oppottunities for unknown nlztabolites to exert their devilish actions ELIieu a%PV.G ible lo urn approa&s
up. n have
ir cle;tr that h>th their advantrg,.
Aithough the truth generally 11~shalf\\+.
tn thtr c;ne n mtght h: Gdr~~bk to duect your drup dcstgn to one of th extreme\. Qtm&8fivemeaanmmth For a memhor of the organuing commntee. n is difficult to prevnt a repon ot ‘ht\’ conference uitbout grvrn~ appropnale account nf all \peaken Let mc only wy that the dircmuy of the contributun~ tF J Z&en on pepttdes. P Be) on enzyme mhibttron. J. K. Seydcl on kmctic* aud P Tunmcrmar~ on +recepon) ua\ es=ntd to tbc Bavour of thrs sympnium And the more dtdacuc kcturer of 1 A. Krenu\hv on enzy-me intubttton and H Ckl~hlager on metabohsm dre better accounted for a full Ien_gthin the \y mprrium proceedinps’ Only a short remark oo tbz prercntatron ot P. J Goodford: -The Quamnauve Slea~ urement of Biological Eftect<*. He Fax e w ovmrw oi the different methods ot mea+ urernent th.n arc requued to e\cablt\h rhz effect of compound\ ;rgarn*t the (relatnel> Gmple .md uell-undentood) maem cab led Suckle Cell DIW;~U t\,~rally ut d cd* like this. the tttcp from haemo&bm wlutton v ta red blood cells to u hole blchti and
TIPS- April/V82
134 vice versa am relatively straightfotward and easy to understand.And even then, he presentedan example where it had taken more than 40 years before an experimental resultfrom the 1910s (which showeda shift of the oxygen saturation curve) could be repeated because of differences in experimentaldesign in the purification pm cedure! Well, after this it looked easy to have your moleculesrotate their substituentsand
turn aroundin fine colours.as Y vonneMartin showedin a shottmovie during the final lectun. It would have been even mom attractiveif shehad not mentionedthe price of an appropriategraphicsterminal . , . At the end I was left with the feeling that we are still a long way fmm tomorrow’s clean and merry drug &sign strategywhich will reploc~ yesterday’s haphazani approach.This symposiumsuppliedample material to cope with today’s mixture of
132
_I
Strategy in drugresearch The Second IUPAC-IUPHAR Symposium, Noordwijkerhout, The Netherlands. To make scientistsfrom diversediscplines tdk IO each other. you organize a sym r&urn with rather diverse presemations witbout parallel sessions.Workers in drug mesearchhave a wide scope of scientific criemation, which generally allow!, them F;* only to keep their job going but alsoto * njol; mostof the lectures presentedat a meeirnglike this. But you take Ihe risk that F.&Hsvtry QSAR-specialist understands ‘@-level presentations on n-receptor fiiocbmistry by Alexander Levitzky and Daphne Atlas., and certain biihmical phammzologistsfail to catch the essenceof a talk on the *lice of predictive calculat. ions by Yvonne Mattin. iiowever. such a symposiumreally createsa fertile environ ment for informal interdisciplin~.~ contacts. Only the neighboutingbulb farmer at one instantexaggeratedthe envimnmental fertility by spreadingexcessiveamoumsof chickendung to fosternext year’s be.rutyof the Dutch landscape.
heldfrom 25 IO 28 August 1981 in
problem. Mefioquine. tiiscovered by the Walter Reed Army Instituteof Re.seatch,is in an advancedstateof development;however. in laboratory situations. resistance can be. developed against this compound Ioo. A new lead is being worked out in collaboration with Chinese scientists. Quing Hao Su or arteannuin,a traditional remedy derived from the plant Artemisia unttuu, containsas the active principle a sesquiterpene lactone(Fig. I ) which is a novel compound in antimalarial therapy’. Chinese scientistsan: testingderivatives of this s-lure, which have shown to be more potentin rheir antimalarial action.
H. Mdhler (Hof&nann-La Roche) gave an overview of the presentthoughtsabut how benzodiazepineswork. In a nutshell, it is assumedthatthe benmdiazepinereceptor is localized in the postsynapticmembrane of the G ABA-trceptor. Here, it is pmbably involved in an allosteric interaction beTo start with. the medicinal chemist was tween the GABA-receptor and the chloride broughtdown to each by Dr Adatokunbo rhanncl. This enhances GABA-ergic 0. Lucas, director of the Special Pmgmm synaptic inhibition in the central nervous in Researchand Training on Tropical Dis system, and Ibe reinforcement of this easesof the WHO in Geneva. When; for physiclogical inhibitory mechanismshould example. an illness like malaria in certain be Ihe mis of the main centraleffectsof Ihe ateas is so persistentthat, even if 99% of benzodiazepines.Of course, much attentthe mosquitoesshould be killed, the in& ion WPSpaid to the recent findings of hen. dence of infection would be still 40 times zodiazepine antagonists(cf. Green rips in higher than‘ the minimal necessary for the issweof last AugustP).It was fascinating transmission,it isclearthat the roleoidmgs lo see in a shon movie the fast effect of is limited. For dealing with tropical dis these compoundsin abolishing the effects easesthe ideal drug shouldbe highly effec- of diazepam on mice, dogs and monkeys. tive, safe, simple to apply ;tnd cheap. More details aboutstructuresand activities Focusing on malaria, the emergence of of these antagonistswere presentedby W. strainsof Plarmodiutn fulciparum which Hunkeler and E. Kyburz ia a poster comate reshtantto 44ninoquinolines and other munication (Fig. 2). drugsin common use. is a mastchallenging A high structural specilicity is shown. Apparently, activity diffe=nces cannot be accounted for in terms of S and R COW figurationaroundthe %carbon in the seven. memberedring. Probably.the conformation of the seven-membeti ring plays a major role. In the discussionatter MBhlefs prs sentation, Ari&s suggestedthat, as these powerful benzodiazepine antagonists do notexert anyeffectsoftheirown. it isquestionable whether an ‘intrinsic’ hem diazcpine receptor ligand does exist. In Mohler’s opinion, we ate all somewhat
1982
brainwashed by the discovery of the endogenous opiate agonists. the endorphins. in this respect. There should be no DPMM (1 priori that an intrinsic receptor agonistexists. Cenainly. thisdebatewill be continued.as in the meantime the isolation otul characterizationof a protein from rat tivsrlewith benzodiazepinereceptoraffinity (‘nephentin’) is repned by people from Wellcome. U.S.A.s. More SLXwith Juacex? J. Knoll hnm Budapes had no problems in attractingattention with his story on the selective MAOB inhibitor (- )deprenyl (Jumexs). He put forward the hypothesis that, if the age-dependentappearance of
KS0 ~1000
!Cmjo’6,4
parkinsonian symptoms and ‘involutional depression’can be attributed IO a decnaie of dopamine (and perhaps other trace amines) in the bruin, other age+dependent symptoms like the decline in male sexual vigor might be a consequenceof the same biochemical event. (Was he peraaps also triggeredby the latter effect beink 3 notorious side effect in the LDDPA-therapy of parkinsonism?). Well, the selective MAaB inhibitor (-)iieprenyl exerts its action by increasing selectively the ‘brain levels of dopamine. So why not test tbis hypothesisby administering (-)deprenyi to old, male, sexually sluggishrats? And indeed, a highly signifEant increasein sexual activity, scored as the numberof intm missionsper minute and the appearanceof
TIPS -April
IV82
CH;I-$H-~)I-CH~-CECH CHg CH3 deprenyl
0 ’
’ CH2-CH-fj-CH2-CECH tH3 CH3 U-1424
ejaculations, was found. However. this attractive simple picture was complicated by the findings with compound U- 1424 (Fig. 3). This is a ‘pure’ MAO~inhibitot. devoid of either calecholamine releasing or motto amine uptake inhibiting effects. and its ineffectivity to give a similar increase in sexual activity suggested thal t - hleprenyl exerts its aphtodisiae effect probably by another mechanism (m-uptake inhibition?). Anyway. as the mean age of Knoll’s audiince was on the declining side of his mean sexual vigor curve. a vigorous di5 cussion was smrted. Further resulb are eagerly awaited.
Drugs: softor SIPble? Originally. it was not aimed to have in the session on ‘Toxicolopical Parameters as a lead a performance of both N. B&r. the promoter of the Soft Drug Approach. and the ‘hard drug’ advocate. E. J. Ariens. but as the planned contribution on N.nitrosamines by R. Preussmann was cancelled because of an unforttmate accident. the organizing committee was glad to find Ariens willing to substitute. So an interesting debate between two different concepts was offeted. Bodor stated that a predictable in Vito destruction to nontoxic moieties is to be preferred. One of the prim ary concepts is to avoid most oxidative metabolism - which mostly ~IXS thmugh highly reactive intermediates-but to use as much as possible dte hydrolytic mechan. isms. e.g. the various esterases. A simple
example is the replacement of the bacteria static cetylpyridinium chloride by an estercontaining analog (Fig. 41.
CH,(CH2),zCH?CH~CH2i;Jo 3
Cl-
CH3(CH$,Z-$-
CI-
0
0 -CH$j
A lot of endogenous substances tsteroid hormones. dopsmine) can be conbidercul as natural utft drups. uncc the huly has developed cffiient. fast and safe metabolic ways for tlir rcmovat. So if. for cxampte. a steroid hormntc can bc released at w-h a rate that tt can be coped with by the normal metabolhm of the body. you c.ut talk of a prodrug-soft drug combination. On tbe other hand. you can look at tbc ihicttve metabohtes and generate a precursor which resembles the active compound Taking hydrocottisotte for examp!e. some interecting examples were shown (Fip. S). After this presentation. Art&s also sue+sed the necessity of petting drug metabolism undercontml. However. he started from the viewpoint: ‘drug metabolism is dtug waste’ (Fig. 6). Non-metabolizable. highly active compounds have to be admuustcrcd in very small quantities only. making the oppottunities for unknown nlztabolites to exert their devilish actions ELIieu a%PV.G ible lo urn approa&s
up. n have
ir cle;tr that h>th their advantrg,.
Aithough the truth generally 11~shalf\\+.
tn thtr c;ne n mtght h: Gdr~~bk to duect your drup dcstgn to one of th extreme\. Qtm&8fivemeaanmmth For a memhor of the organuing commntee. n is difficult to prevnt a repon ot ‘ht\’ conference uitbout grvrn~ appropnale account nf all \peaken Let mc only wy that the dircmuy of the contributun~ tF J Z&en on pepttdes. P Be) on enzyme mhibttron. J. K. Seydcl on kmctic* aud P Tunmcrmar~ on +recepon) ua\ es=ntd to tbc Bavour of thrs sympnium And the more dtdacuc kcturer of 1 A. Krenu\hv on enzy-me intubttton and H Ckl~hlager on metabohsm dre better accounted for a full Ien_gthin the \y mprrium proceedinps’ Only a short remark oo tbz prercntatron ot P. J Goodford: -The Quamnauve Slea~ urement of Biological Eftect<*. He Fax e w ovmrw oi the different methods ot mea+ urernent th.n arc requued to e\cablt\h rhz effect of compound\ ;rgarn*t the (relatnel> Gmple .md uell-undentood) maem cab led Suckle Cell DIW;~U t\,~rally ut d cd* like this. the tttcp from haemo&bm wlutton v ta red blood cells to u hole blchti and
TIPS- April/V82
134 vice versa am relatively straightfotward and easy to understand.And even then, he presentedan example where it had taken more than 40 years before an experimental resultfrom the 1910s (which showeda shift of the oxygen saturation curve) could be repeated because of differences in experimentaldesign in the purification pm cedure! Well, after this it looked easy to have your moleculesrotate their substituentsand
turn aroundin fine colours.as Y vonneMartin showedin a shottmovie during the final lectun. It would have been even mom attractiveif shehad not mentionedthe price of an appropriategraphicsterminal . , . At the end I was left with the feeling that we are still a long way fmm tomorrow’s clean and merry drug &sign strategywhich will reploc~ yesterday’s haphazani approach.This symposiumsuppliedample material to cope with today’s mixture of