- Email: [email protected]
The team approach or doing without genius
TIPS - May,
1980
225
recently been applied to problems in pharmacology”. This model can account for several phenomena: apparent heterogeneity of receptor, positive or negative cooperativity, non-linear coupling and activation, and biphasic dose response curves (analogous to substrate inhibition for enzymes, as classically described by Haldane). This model can also account for the action of partial agonists and, competitive, non-competitive and ‘mixed’ antagonists. This model is closely related to the ‘zipper’ model as discussed at the conference by A. S. V. Burgen and coworkers’*. The importance of ‘accessory sites’ in generating the high affinity frequently observed for antagonists was discussed by several participants, including Ariens, Burgen, Marshall, myself, and J. Hanoune of INSERM. Paris. Hanoune noted that the introduction of a bulky, hydrophobic moiety can transform a /3-adrenergic agonist into an u-adrenergic antagonistiq, thus raising new questions about the relationships between u- and /I-adrenoceptors.
The Titisee International Conference brought together a wide variety of approaches and disciplines, ranging from classical pharmacology to enzymology,
membrane biology, mathematical modeling, molecular modeling, and multidisciplinary ‘receptorology’ for drugs, neurotransmitters, steroids, peptides. and antibodies. Although the ultimate understanding of these distinctions between agonists and antagonists must (by definition) remain elusive. the participants emerged from the meeting with a spirit of positive cooperativuy and with a better appre:iation of many of the current central issues and of tne general strategic avenues which promise to be rewarding. DAVID RODBARD Biophysrcrd and
Enoocrrnolo~v
Reproduction
Institute National 20205.
n/ Chrld !rstitutes
.Sectron,
Research Health
and Human
o,’ ileakh.
Endocrmology
Branch,
Bethesda,
and Brother
Ltd.,
Huntercombe
Lane
14
Kent. R. S., De L-an. A. and Lei)row~tz. R J (19aU) ,I#ol. Pharmacol. 17. 14-23 2 Lk Learr. A.. Munson. P. and Rodbard, D. (1978) 4m. J. Physrol. 235. E97-El02 3 Birds&, N. J. M.. Burgen, A. 5. V. and Hulme. E. C. (1978) Uol. Pharmacol. 14.723-726 4 Burgermeister. W.. Klein, W. L.. Xrenbe:g. N. and Witkop, 8. (1978) Mol. Pharmwoi. 14.
I
75 I-767
South,
Feldman, H. A. (197Z)Anal. Biochem.
Taplow.
Maidenhead.
Functron.
Mewoevrdocrtne
and
Asperrs
and EroRenolL;
(way. E. cd.).
opil~e
agonrstr and
Pergamon Press. Veu
York Chang. K. J. and Cuatrecasas. P
I 1979) J
Biol.
234.2610-2618
I5 Weaver. D. C . Barr>. C. D.. McDaruel. 51 I %larshall. G. R. and Lat... P. E (1979) 4’,/
Reading list
317-338
Berkshire
U6
OPH.
U.K.
It is easy to be objective about the poor innovational record of the academic pharmacologist in finding new drugs but it is impossible to be objective about the cause. Accepting that, 1 feel it is not unbecoming for a medicinal chemist to voice his opinions in wuat is a rather remarkable state of affairs. While 1 rm name several eminent contemporary pharmacologists both academic and industrial whose first degree was in chemistry, 1 cannot, for the life of me, name one prastising medicinal
Endoacnou antagonists
Chem
5
Bram
(Goldstem. M. rd. 1. pp.l03-I IS. Raven Press. New York I3 Pert. C. B. and Taylor. D. P (1979) m
Maryland
J. F. Cavalla Wpth
and
Neuropsychratrtc
r%ationol
L . S. A.
A . De Lean. A L. and 1 efkour~r.
R. J. (1979) Mol. Pharmacol lb. I -9 7 Munwn. P 1. and Robard. 0 (1979) Endocrrnolo~~ 105. 1377-13131 g Anens. E J.. Eeld. A J.. Rodrigue\ de Miwtda. J. F. and Slmomr. A M. (1979) m The Receprors(0’Brien.R. D.ed.)Vol. I. pp 33-91. Plenum Press. New York 9 Greenberg. D. A. hnd Snyder. S. H. (1978) Mol. Pharmacol. 14.38 49 IO U’Prichard, D. C.. Charncsr. M. E.. Roberrson. D. and Snyder. S. H. (1978) Eur. J. Pharmacol. 50.87-89 I I U’Prichard. D. C. and Snyder, S H. 41979) f.& Std. 24.79-88 12 U’Pnchard. D. C. (19791 m Ergor Compounds
Development,
The team approach or doing without genius John
6 Hancock.A.
chemist whose early training was in pharmacology. It is not that pirarmacologists lack interest in the science of chemistry; many are passionate devotees of its mysteries, but the fact remains that the formal transfer from pharmacology into chemistry today .eems a difticult one to mr?ke. Before the war and, by definition, prior to the massive growth of the research effort of the pharmaceutical industry it was the academic pharmacologist who was responsible for the discovery of new
Pharmacol.
.
lb. 361-;bB
Marshall. G. R. (1979) m Medronol Chem. ir+ V/(Simkms. M. A. cd.). pp. 225-235. Cotsuold Press Ltd. Oxford I7 De Lean. A.. Munson. P. J. and Rodbard, D (1979) .Hof. Pharmacol. IC, 60-70 18 Burgen. A 5. V.. Roberts. G. C. K. and Fecnek. J. (1975) harum iL ondo*/ 253. 753-‘55 19 Aggerbeck. M., Guelhen. G. and Hanoune. J. (1979) Br. 1. fharmmoi. 65. 155-159 I6
medicines. While one cannot be certain that Ehrlich was personally responsible for the synthesis of 3.3’-diamino-4,4 dihydroxyarsenobenzene he was undoubtedly involved in the chemistry that led up to it. Similarly Bovet was closely associated with the design of the early antihistamines and in the same vein it is pertinent to recall that Sir Henry Dale was appointed to \he Chair of Chemistry at the Royal Institution at the age of sixrysever.
Of course, one should n3t labour the point. Many reading this will be able IO evidence exceptions to the trend. My reason for putting it forward is IO highlight a more compelling observation concerning the genesis of drjg discoveries today, namely that it is becoming progressively more evident that new drugs emerge from the pharmaceutical industry and fewer from out of the academic world. One immediate explauation for this lies in the enormous amount of SO called
226 ‘safety’ work (much of it purely regula- those of pharmacology, But even when &ory)which must be completed before a they are in the same building (1 am thinknew conmound is allowed to enter man %ng here of Schools of Pharmacy), _.. ._~~~ or, even more, befare it enters a patient. personaJ observation suggests that the is not taken the desirabie need (or ot~i~) f*r such op~rtunity for ~~~a~ati~ horrendous effort would form tbe sub- as dete~~n~iy as one miqbt hope. Why stance of another article. My view, how- is this? The research programmc involved in ever, is that it is not the whole nor even the main ;eason why academia is the identification of a new drug does not, currently so detIch!nt in producu% new of necessity, have to be replete with science in ah areas. mcdi&es. The cause for that iitf much i~ovation~ more in the way tbe various branches Of Frequently the animal model of the the science of drug discovery have become disease entity is already known and sometimes, as in the microbiological tieid, compartmentalized and overspeciaPted. Goldsmith stood amazed that the more or less obvious. Only when a novel Village Schoolmaster’s ‘One small bead physioloffical process is being explored could carry all he knew’! Were be alive does breakthrough science become today be would no doubt gaze and invoautd. In such cases the p~~a~~~ the keystone of the cbwonder more at the degree and detail of is f~u~t~y the average scademic’s teaming rather labllrative endeavour and the pharmathan at its breadth, Today only the poly- cologist cau justly be regarded as the math can cover all the facets necessary for prime inventor with the chemist as his aid. tbe broadly based innovational study of Clearly work of this character would drug research. Such people are vanish- interest ahnost any academic pharmacoloing& few in number and when identified gist whether working with 8 chemist or novel pharmacoare tbemseJvesfrequently seduced into the not. Unf~~~ateJy~ rewarding pools of specialization. As a logical discovery processes occur only result the science of drug discovery has rsasly and even when they do emerge it is tome to terms with the situation and often only the starting point for the main combined the t&nts of several disciplines u&k ahead. Jr is only when tbe bioJogicaJ screen is into a composite discovery team: the &xnin to make, the pha~~~u~i~ to identified and set up that the need for test identify, the toxicologist to vouchsafe and compounds to fuet it becomes apparent. the pharmacist to dispense. Central to the At this stage some phartnacologists lose success of such a team is the active heart with the work, feellug their talents working combination of chemist and are beintf abused in undertaking ‘routine pharmacologist without whose initial screening’. While this attitude is under~~~r~tion no work wit1derive for the standabhzit is not realty r;tfcnsible. Surely other’s attention. the worth of the end product justifies the in industry, of cotxse, people are paid repetitive character-of some of the work to collaborate, paid to sacrifice their that leads up to its identif&ttion? In the natural idiosyncratic ambitions for the excitement of the chase for, say, a totally greazer giory of the team. It will not do to new anti-inf&3mmatory, one that reverses dwell too long on the motivation such the bony changes of a long standing payment produces. In the view of some, arthritis rather than simp& ~l~ia~ng the the mtsny is secondary to the driving worst excesses of ~~~ati~ for enthusiasm engendered by the quest but, example, the routine evaluation of a series for all that, the spur of monetary reward or compounds is 110chore, Nevertheless. should not be disregardednor diminished. sumc academic pharmacologists might WJtiJccash does not bring contentment it regard it as such. at least allows tbe scientist to be disconAt the same time, the academic tented in comfort. chemist, as!ium& he has been identi&d. But what of the academic pbarma- v&l need ali the ~persuadiig the biologist dogist and chemist? Why cannot they GUImuster to start a cotibotative work r;ollaboratedwonately in like mner pr~gratttm~ in the first place. AU is well if to their indtsstrirrl~dlcagues? Wfl mme the compounds required have already of -, the mhodty alas, do cob&- bren made, provided aiways that the orate. The m&3&y, bowever, beat tbeh Pharmacofcsisr is asking on& for microselparate paths to ever more recondite gram quatttfties_ Troubles &om when a pastura. CfearY, geographical factors rWueS is made for more materi& for loom targe iu this failure to collaborate. tens or even hundreds of grams of subFCWtinivmitia can boast of having the stance. Work of that characmr is seldom chemistry stories contiguous with publishable and only infrequently passes
muster as fodder for a Ph.D. thesis, fn the same way when activity is found with the Peru-chloro-derivative, Heaven forfend if the pharmacologist should request the ~~-~orno, the parzl-methy& the guruhydroxy undso W&&Y.Such work, they say, is heck work. Never mind if it turns out to be a cure for ctmcer. the essence of the chemistry must be its publishability since without that tbc academic chemist perishes aiong with the patient. Qn another plane, the occasional departure of ProfessionaT pharmacelot&al talent from the ‘groves of Academe’ to the ‘desert wastes’ of drug house laboratories need not be too much lamented provided it does not obtund on the continued production of good pharmacok~gy graduates. Such moves in recent years have proved highly beneficial both to the companies involved and to the scientists making the move. It is not a one way traffic. Quite a few professorial Chairs have been f&d, ilhrstriously, direct from ~~ust~~ benches. Such cross feniliration is to be w&corned provided, again, that it does not go too far in any one direction. In this regard it will be necessary for great caution to he exercised when university swtbacks in expenditure arc?made that an excessive indugmce in FEscaicontrc3 does not &ad to a diaspora of biological tateat from out of the universities. It is a foolhardy economy which saves pennies by consuming too great a share of the seed corn, especially in a country like Great Britain where the research-based ph~a~tic~ industry remains one of our major exporters, From the academic chemist I fear we c&&nexpect little more than they are currently giving us, While one can cite the splendid achievements of the past when ltkVeschf made ~~~y~rne~ He&i& Smith norgestref and Abraham the c~h~~~~~ the stage today seems bare. It is strange that this should be so since &tpite the reluctance of the ecadetnics to work as a te=m it is a very simpie matter for the average chemist to get his new compounds scmened. This will often be 34foneon request by almost any pharmaceuticaI resetuch laboratory as well as by certain U.S. Governmentat a&trtcies currently offering widespread screening facilities for cancer, anticonVutsaats amdtropic& rnedi&nea. C&c;area that does excite a staaving aca&mfc b&rest is the study of Quantitative Strnctttre Actfvity Relationships and the hope is always there that one day even this C&ristmas cactus wfll blmm. Ln truth, it is getttqg more difficult,
TIPS-May,
1980
227
longer, more expensive and less rewarding to discover new medicines. The halycon
days are past am\ the future looks greyish if not positively grey. Yet despite that, or possibly because of that, the total investment of men and money in industrial drug research is greater now in real terms than ever it has been in the past. In such circumstances the failure of academic pharmacologists and chemists to work together must be lamented. Talent is wasted when not put to best use. In universities and Schools of Pharmacy up and down the country the possibility of collaboration between the two disciplines is going unregarded and in this respect the fault must lie at the pharmacologist’s door. If the chemist is not made aware of the presence of a motivated pharmacologist in his vicinity actively seeking the novel compounds he is making and urgently wishing to effect a collaboration it is unlikely that the chemist will make the first move himself. With the work that needs to be done such pharmacologicail dereliction cannot be afforded. The time for insularity is past.
The leukotrienes:a nevw group of biologically active compounds including SRS-A Bengt Samuelsson &parmwIt :I?
Chemistry. Karolinska In.Wutet, S104 01 .Crockholm, sw&~.
,..
Evidence fa; a central role of arachidonic acid as precursor of regulators and mediators of various cell functions has accumulated during the past few years. the enzyme cycle-oxygenase Thus, catalyses formation of the endoperoxides PGG, and PGH,, which can be transformed into various prostaglandins and thromboxanes (Fig. 1)‘. In connection with studies leading to the discovery of thromboxanes in human platelets a noncycle-oxygenase catalysed pathway of arachidonic acid transformation was detected. The product, 1%HE?%, was formed by a Ii-nxygenase. which was not non-steroidal antiinhibited inflammator) irugs. In view of the possible role of transformation products of arachidonic acid in inflammatory reacrions we decided to extend our metabolic studies to leukocytes. The development of I bypotkis Rabbit polymorphonuclur !eukocytes obtainti from the peritoneal cavity after
3ohn CavaUe was o founder member of the Soriety Research ond l-iwsum for IO years before becoming its Choirmon. Currmtly, he is Choinnon of the Commission on Mu&inol Cketnishy of the Intemationol Union of Pure ond Applied Ckemirtry. He has b&n in U.K. drug rscoIch for WV-:: ;O yean,J%sf with Rake Davis and now with Wyeth Labomtaria where he is Director of Research & Ikwloptnent.
for Drug
injection of glycogen were incubated with labelled arachidonic acid. The major product was identified as S(S)-hydroxy63, I I, ICeicosatetraeno, : acid (5HETE), however, it was evident that more ;jolar products were &JO formed. These were identified as 5(S). :2(R)dihydrox~d.8,10. M-eicosatetraenoic atid (major product) (leukotnene B. cf. I2 below), two additic-11 5(S). dihydroxy-6,8,10-rrans14-c&-eicosatetraenoic acids, epimerls at C-12. and two diastereoisomeric 56dihydroxy7,9,11,14_eicosatetraenoic acids. The steric analysis, showing formation of two acids with an all frarzs conjugated triene. epimeric at C-12 and one major isomer (ItR) wirh different configuration of the of the triene raised the question mechanism of formation. Isotopic oxygen experiments demnnstrated that the oxygen of the alcohol group at C-5 originated in molecular oxygen, whereas the oxygen of the akohql group at C-12 was derived from water. These bindings
PHOSPHOLIPASE ARACHI~JO’NIC AC!D----rl2
t15)-HPETE
----
12(‘5)-?-+ETE
__* $iPET;’ ,
PROSTAGLANZ!NS
&PETE
-
*5-HETE
-
AND THROMEIOXANES
LEUKOTRIENES
Fig. I. Tmn$wmarion of arachidonic acid intogmstaglandm.% thrombaxancs end feuko:runrJ.
1980
225
recently been applied to problems in pharmacology”. This model can account for several phenomena: apparent heterogeneity of receptor, positive or negative cooperativity, non-linear coupling and activation, and biphasic dose response curves (analogous to substrate inhibition for enzymes, as classically described by Haldane). This model can also account for the action of partial agonists and, competitive, non-competitive and ‘mixed’ antagonists. This model is closely related to the ‘zipper’ model as discussed at the conference by A. S. V. Burgen and coworkers’*. The importance of ‘accessory sites’ in generating the high affinity frequently observed for antagonists was discussed by several participants, including Ariens, Burgen, Marshall, myself, and J. Hanoune of INSERM. Paris. Hanoune noted that the introduction of a bulky, hydrophobic moiety can transform a /3-adrenergic agonist into an u-adrenergic antagonistiq, thus raising new questions about the relationships between u- and /I-adrenoceptors.
The Titisee International Conference brought together a wide variety of approaches and disciplines, ranging from classical pharmacology to enzymology,
membrane biology, mathematical modeling, molecular modeling, and multidisciplinary ‘receptorology’ for drugs, neurotransmitters, steroids, peptides. and antibodies. Although the ultimate understanding of these distinctions between agonists and antagonists must (by definition) remain elusive. the participants emerged from the meeting with a spirit of positive cooperativuy and with a better appre:iation of many of the current central issues and of tne general strategic avenues which promise to be rewarding. DAVID RODBARD Biophysrcrd and
Enoocrrnolo~v
Reproduction
Institute National 20205.
n/ Chrld !rstitutes
.Sectron,
Research Health
and Human
o,’ ileakh.
Endocrmology
Branch,
Bethesda,
and Brother
Ltd.,
Huntercombe
Lane
14
Kent. R. S., De L-an. A. and Lei)row~tz. R J (19aU) ,I#ol. Pharmacol. 17. 14-23 2 Lk Learr. A.. Munson. P. and Rodbard, D. (1978) 4m. J. Physrol. 235. E97-El02 3 Birds&, N. J. M.. Burgen, A. 5. V. and Hulme. E. C. (1978) Uol. Pharmacol. 14.723-726 4 Burgermeister. W.. Klein, W. L.. Xrenbe:g. N. and Witkop, 8. (1978) Mol. Pharmwoi. 14.
I
75 I-767
South,
Feldman, H. A. (197Z)Anal. Biochem.
Taplow.
Maidenhead.
Functron.
Mewoevrdocrtne
and
Asperrs
and EroRenolL;
(way. E. cd.).
opil~e
agonrstr and
Pergamon Press. Veu
York Chang. K. J. and Cuatrecasas. P
I 1979) J
Biol.
234.2610-2618
I5 Weaver. D. C . Barr>. C. D.. McDaruel. 51 I %larshall. G. R. and Lat... P. E (1979) 4’,/
Reading list
317-338
Berkshire
U6
OPH.
U.K.
It is easy to be objective about the poor innovational record of the academic pharmacologist in finding new drugs but it is impossible to be objective about the cause. Accepting that, 1 feel it is not unbecoming for a medicinal chemist to voice his opinions in wuat is a rather remarkable state of affairs. While 1 rm name several eminent contemporary pharmacologists both academic and industrial whose first degree was in chemistry, 1 cannot, for the life of me, name one prastising medicinal
Endoacnou antagonists
Chem
5
Bram
(Goldstem. M. rd. 1. pp.l03-I IS. Raven Press. New York I3 Pert. C. B. and Taylor. D. P (1979) m
Maryland
J. F. Cavalla Wpth
and
Neuropsychratrtc
r%ationol
L . S. A.
A . De Lean. A L. and 1 efkour~r.
R. J. (1979) Mol. Pharmacol lb. I -9 7 Munwn. P 1. and Robard. 0 (1979) Endocrrnolo~~ 105. 1377-13131 g Anens. E J.. Eeld. A J.. Rodrigue\ de Miwtda. J. F. and Slmomr. A M. (1979) m The Receprors(0’Brien.R. D.ed.)Vol. I. pp 33-91. Plenum Press. New York 9 Greenberg. D. A. hnd Snyder. S. H. (1978) Mol. Pharmacol. 14.38 49 IO U’Prichard, D. C.. Charncsr. M. E.. Roberrson. D. and Snyder. S. H. (1978) Eur. J. Pharmacol. 50.87-89 I I U’Prichard. D. C. and Snyder, S H. 41979) f.& Std. 24.79-88 12 U’Pnchard. D. C. (19791 m Ergor Compounds
Development,
The team approach or doing without genius John
6 Hancock.A.
chemist whose early training was in pharmacology. It is not that pirarmacologists lack interest in the science of chemistry; many are passionate devotees of its mysteries, but the fact remains that the formal transfer from pharmacology into chemistry today .eems a difticult one to mr?ke. Before the war and, by definition, prior to the massive growth of the research effort of the pharmaceutical industry it was the academic pharmacologist who was responsible for the discovery of new
Pharmacol.
.
lb. 361-;bB
Marshall. G. R. (1979) m Medronol Chem. ir+ V/(Simkms. M. A. cd.). pp. 225-235. Cotsuold Press Ltd. Oxford I7 De Lean. A.. Munson. P. J. and Rodbard, D (1979) .Hof. Pharmacol. IC, 60-70 18 Burgen. A 5. V.. Roberts. G. C. K. and Fecnek. J. (1975) harum iL ondo*/ 253. 753-‘55 19 Aggerbeck. M., Guelhen. G. and Hanoune. J. (1979) Br. 1. fharmmoi. 65. 155-159 I6
medicines. While one cannot be certain that Ehrlich was personally responsible for the synthesis of 3.3’-diamino-4,4 dihydroxyarsenobenzene he was undoubtedly involved in the chemistry that led up to it. Similarly Bovet was closely associated with the design of the early antihistamines and in the same vein it is pertinent to recall that Sir Henry Dale was appointed to \he Chair of Chemistry at the Royal Institution at the age of sixrysever.
Of course, one should n3t labour the point. Many reading this will be able IO evidence exceptions to the trend. My reason for putting it forward is IO highlight a more compelling observation concerning the genesis of drjg discoveries today, namely that it is becoming progressively more evident that new drugs emerge from the pharmaceutical industry and fewer from out of the academic world. One immediate explauation for this lies in the enormous amount of SO called
226 ‘safety’ work (much of it purely regula- those of pharmacology, But even when &ory)which must be completed before a they are in the same building (1 am thinknew conmound is allowed to enter man %ng here of Schools of Pharmacy), _.. ._~~~ or, even more, befare it enters a patient. personaJ observation suggests that the is not taken the desirabie need (or ot~i~) f*r such op~rtunity for ~~~a~ati~ horrendous effort would form tbe sub- as dete~~n~iy as one miqbt hope. Why stance of another article. My view, how- is this? The research programmc involved in ever, is that it is not the whole nor even the main ;eason why academia is the identification of a new drug does not, currently so detIch!nt in producu% new of necessity, have to be replete with science in ah areas. mcdi&es. The cause for that iitf much i~ovation~ more in the way tbe various branches Of Frequently the animal model of the the science of drug discovery have become disease entity is already known and sometimes, as in the microbiological tieid, compartmentalized and overspeciaPted. Goldsmith stood amazed that the more or less obvious. Only when a novel Village Schoolmaster’s ‘One small bead physioloffical process is being explored could carry all he knew’! Were be alive does breakthrough science become today be would no doubt gaze and invoautd. In such cases the p~~a~~~ the keystone of the cbwonder more at the degree and detail of is f~u~t~y the average scademic’s teaming rather labllrative endeavour and the pharmathan at its breadth, Today only the poly- cologist cau justly be regarded as the math can cover all the facets necessary for prime inventor with the chemist as his aid. tbe broadly based innovational study of Clearly work of this character would drug research. Such people are vanish- interest ahnost any academic pharmacoloing& few in number and when identified gist whether working with 8 chemist or novel pharmacoare tbemseJvesfrequently seduced into the not. Unf~~~ateJy~ rewarding pools of specialization. As a logical discovery processes occur only result the science of drug discovery has rsasly and even when they do emerge it is tome to terms with the situation and often only the starting point for the main combined the t&nts of several disciplines u&k ahead. Jr is only when tbe bioJogicaJ screen is into a composite discovery team: the &xnin to make, the pha~~~u~i~ to identified and set up that the need for test identify, the toxicologist to vouchsafe and compounds to fuet it becomes apparent. the pharmacist to dispense. Central to the At this stage some phartnacologists lose success of such a team is the active heart with the work, feellug their talents working combination of chemist and are beintf abused in undertaking ‘routine pharmacologist without whose initial screening’. While this attitude is under~~~r~tion no work wit1derive for the standabhzit is not realty r;tfcnsible. Surely other’s attention. the worth of the end product justifies the in industry, of cotxse, people are paid repetitive character-of some of the work to collaborate, paid to sacrifice their that leads up to its identif&ttion? In the natural idiosyncratic ambitions for the excitement of the chase for, say, a totally greazer giory of the team. It will not do to new anti-inf&3mmatory, one that reverses dwell too long on the motivation such the bony changes of a long standing payment produces. In the view of some, arthritis rather than simp& ~l~ia~ng the the mtsny is secondary to the driving worst excesses of ~~~ati~ for enthusiasm engendered by the quest but, example, the routine evaluation of a series for all that, the spur of monetary reward or compounds is 110chore, Nevertheless. should not be disregardednor diminished. sumc academic pharmacologists might WJtiJccash does not bring contentment it regard it as such. at least allows tbe scientist to be disconAt the same time, the academic tented in comfort. chemist, as!ium& he has been identi&d. But what of the academic pbarma- v&l need ali the ~persuadiig the biologist dogist and chemist? Why cannot they GUImuster to start a cotibotative work r;ollaboratedwonately in like mner pr~gratttm~ in the first place. AU is well if to their indtsstrirrl~dlcagues? Wfl mme the compounds required have already of -, the mhodty alas, do cob&- bren made, provided aiways that the orate. The m&3&y, bowever, beat tbeh Pharmacofcsisr is asking on& for microselparate paths to ever more recondite gram quatttfties_ Troubles &om when a pastura. CfearY, geographical factors rWueS is made for more materi& for loom targe iu this failure to collaborate. tens or even hundreds of grams of subFCWtinivmitia can boast of having the stance. Work of that characmr is seldom chemistry stories contiguous with publishable and only infrequently passes
muster as fodder for a Ph.D. thesis, fn the same way when activity is found with the Peru-chloro-derivative, Heaven forfend if the pharmacologist should request the ~~-~orno, the parzl-methy& the guruhydroxy undso W&&Y.Such work, they say, is heck work. Never mind if it turns out to be a cure for ctmcer. the essence of the chemistry must be its publishability since without that tbc academic chemist perishes aiong with the patient. Qn another plane, the occasional departure of ProfessionaT pharmacelot&al talent from the ‘groves of Academe’ to the ‘desert wastes’ of drug house laboratories need not be too much lamented provided it does not obtund on the continued production of good pharmacok~gy graduates. Such moves in recent years have proved highly beneficial both to the companies involved and to the scientists making the move. It is not a one way traffic. Quite a few professorial Chairs have been f&d, ilhrstriously, direct from ~~ust~~ benches. Such cross feniliration is to be w&corned provided, again, that it does not go too far in any one direction. In this regard it will be necessary for great caution to he exercised when university swtbacks in expenditure arc?made that an excessive indugmce in FEscaicontrc3 does not &ad to a diaspora of biological tateat from out of the universities. It is a foolhardy economy which saves pennies by consuming too great a share of the seed corn, especially in a country like Great Britain where the research-based ph~a~tic~ industry remains one of our major exporters, From the academic chemist I fear we c&&nexpect little more than they are currently giving us, While one can cite the splendid achievements of the past when ltkVeschf made ~~~y~rne~ He&i& Smith norgestref and Abraham the c~h~~~~~ the stage today seems bare. It is strange that this should be so since &tpite the reluctance of the ecadetnics to work as a te=m it is a very simpie matter for the average chemist to get his new compounds scmened. This will often be 34foneon request by almost any pharmaceuticaI resetuch laboratory as well as by certain U.S. Governmentat a&trtcies currently offering widespread screening facilities for cancer, anticonVutsaats amdtropic& rnedi&nea. C&c;area that does excite a staaving aca&mfc b&rest is the study of Quantitative Strnctttre Actfvity Relationships and the hope is always there that one day even this C&ristmas cactus wfll blmm. Ln truth, it is getttqg more difficult,
TIPS-May,
1980
227
longer, more expensive and less rewarding to discover new medicines. The halycon
days are past am\ the future looks greyish if not positively grey. Yet despite that, or possibly because of that, the total investment of men and money in industrial drug research is greater now in real terms than ever it has been in the past. In such circumstances the failure of academic pharmacologists and chemists to work together must be lamented. Talent is wasted when not put to best use. In universities and Schools of Pharmacy up and down the country the possibility of collaboration between the two disciplines is going unregarded and in this respect the fault must lie at the pharmacologist’s door. If the chemist is not made aware of the presence of a motivated pharmacologist in his vicinity actively seeking the novel compounds he is making and urgently wishing to effect a collaboration it is unlikely that the chemist will make the first move himself. With the work that needs to be done such pharmacologicail dereliction cannot be afforded. The time for insularity is past.
The leukotrienes:a nevw group of biologically active compounds including SRS-A Bengt Samuelsson &parmwIt :I?
Chemistry. Karolinska In.Wutet, S104 01 .Crockholm, sw&~.
,..
Evidence fa; a central role of arachidonic acid as precursor of regulators and mediators of various cell functions has accumulated during the past few years. the enzyme cycle-oxygenase Thus, catalyses formation of the endoperoxides PGG, and PGH,, which can be transformed into various prostaglandins and thromboxanes (Fig. 1)‘. In connection with studies leading to the discovery of thromboxanes in human platelets a noncycle-oxygenase catalysed pathway of arachidonic acid transformation was detected. The product, 1%HE?%, was formed by a Ii-nxygenase. which was not non-steroidal antiinhibited inflammator) irugs. In view of the possible role of transformation products of arachidonic acid in inflammatory reacrions we decided to extend our metabolic studies to leukocytes. The development of I bypotkis Rabbit polymorphonuclur !eukocytes obtainti from the peritoneal cavity after
3ohn CavaUe was o founder member of the Soriety Research ond l-iwsum for IO years before becoming its Choirmon. Currmtly, he is Choinnon of the Commission on Mu&inol Cketnishy of the Intemationol Union of Pure ond Applied Ckemirtry. He has b&n in U.K. drug rscoIch for WV-:: ;O yean,J%sf with Rake Davis and now with Wyeth Labomtaria where he is Director of Research & Ikwloptnent.
for Drug
injection of glycogen were incubated with labelled arachidonic acid. The major product was identified as S(S)-hydroxy63, I I, ICeicosatetraeno, : acid (5HETE), however, it was evident that more ;jolar products were &JO formed. These were identified as 5(S). :2(R)dihydrox~d.8,10. M-eicosatetraenoic atid (major product) (leukotnene B. cf. I2 below), two additic-11 5(S). dihydroxy-6,8,10-rrans14-c&-eicosatetraenoic acids, epimerls at C-12. and two diastereoisomeric 56dihydroxy7,9,11,14_eicosatetraenoic acids. The steric analysis, showing formation of two acids with an all frarzs conjugated triene. epimeric at C-12 and one major isomer (ItR) wirh different configuration of the of the triene raised the question mechanism of formation. Isotopic oxygen experiments demnnstrated that the oxygen of the alcohol group at C-5 originated in molecular oxygen, whereas the oxygen of the akohql group at C-12 was derived from water. These bindings
PHOSPHOLIPASE ARACHI~JO’NIC AC!D----rl2
t15)-HPETE
----
12(‘5)-?-+ETE
__* $iPET;’ ,
PROSTAGLANZ!NS
&PETE
-
*5-HETE
-
AND THROMEIOXANES
LEUKOTRIENES
Fig. I. Tmn$wmarion of arachidonic acid intogmstaglandm.% thrombaxancs end feuko:runrJ.