Biochemical Pharmacology 98 (2015) 360–362

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A tribute to David Triggle Walter H. Moos a,b,c,* a

SRI Biosciences, a Division of SRI International, Menlo Park, CA, USA University of California, San Francisco, CA, USA c James Madison University, Harrisonburg, VA, USA b


Article history: Received 20 April 2015 Accepted 21 April 2015 Available online 28 April 2015 Keywords: Ion channel Calcium antagonist Cholinergic receptor Medicinal chemistry Bioethics



‘‘A gentleman and a scholar’’ is how many would characterize David Triggle. His insightful, thoughtful approaches to professional pursuits, both personal research and collaborative relationships, stand out by any measure. He has shaped students, colleagues, and whole fields, calcium ion channels and ligands being most representative of the latter. In recent years, he has expanded his contributions to important commentaries on politics and social challenges in the sciences. David is the rare intellect able to do all this and more, as outlined herein. ß 2015 Elsevier Inc. All rights reserved.

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Calcium channel blockers – yes – but wait, there is more!. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

360 360 362

1. Introduction

2. Calcium channel blockers – yes – but wait, there is more!

As you go through life, a very small number of people impress you as being the proverbial ‘‘gentleman and scholar’’. These are the rare men and women of science who know their fields front to back and back again, who are always looking for and finding novel ways to approach important problems while challenging others to ‘‘think different’’ too, who inspire and mold future leaders, and who are willing to stand up for what they believe in—whether science or politics or the topic du jour. From the perspective of a number of interactions from the mid-1980s to the first decade of the new millennium, I conclude that David Triggle is all of the above.

Who else but David Triggle even attempted to cover, in fact pioneer, such broad territory in the history of modern-day medicinal chemistry and pharmacology? Witness the following examples, drawing on some of David’s early forays into many interesting and important areas of science. (Note: Here and elsewhere, I will cite only a few representative articles, since David has made so many contributions to the scientific literature. I will also try to refer back to some of David’s earlier articles rather than his more recent ones, hoping to provide a somewhat older sampling of the history and depth of his work than younger authors might attempt.)

* Corresponding author at: SRI Biosciences, a Division of SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025, USA. E-mail addresses: [email protected], [email protected]

 Ion channels writ large, especially dihydropyridine calcium channel blockers. [1]  Benzodiazepine, benzomorphan, and phencyclidine pharmacology. [2–4]  Antifolates, among other antitumor approaches. [5] 0006-2952/ß 2015 Elsevier Inc. All rights reserved.

W.H. Moos / Biochemical Pharmacology 98 (2015) 360–362

 Cholinesterases and alkylating agents. [6,7]  Smooth muscle physiology, hypertension, and heart failure. [8,9]  Novel adrenergic, dopaminergic, and muscarinic receptor agents. [10]  New aspects of estrogen action and other hormones. [11,12]  Lanthanides and ionophores. [13,14]  The future of the biomedical sciences, as well as the accompanying ethics, ideologies, and social policies. In regard to calcium ion channels, first reported in the mid1960s, David was clearly well on his way to leading the field by 1972 as evidenced in a symposium paper on membranal calcium ion translocation and cholinergic receptor activation [15]. Pharmaceutical scientists who came of age in the 1980s would likely have first learned of David through his pioneering work on ion channels, or vice versa. These were heady days for research on drugs like the dihydropyridine nifedipine, the benzothiazepine diltiazem, and the phenylalkylamine verapamil (Fig. 1), given all of their potential to treat cardiovascular and related conditions. David’s outstanding, detailed reviews on ion channels and ligands rapidly became critical, must-have references for everyone in the field. It is not unusual to see hundreds of citations referring to one Triggle ion channel review article or another. For example, see Janis and Triggle [16]. While I could go into David’s ion channel work in more detail, others will summarize this area more fully in accompanying articles in this special issue. Certain titles in David’s large resume of published articles are quite engaging, indicative of his playful wit. Following are a few of his more provocative contributions:  ‘‘Nous Sommes Tous des Bacteries: Implications for medicine, pharmacology and public health.’’ [17]  ‘‘The chemist as astronaut: searching for biologically useful space in the chemical universe.’’ [18]


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 ‘‘Treating desires not diseases: a pill for every ill and an ill for every pill?’’ [19]  ‘‘Everybody must get cloned: ideological objections do not hold up.’’ [20]  ‘‘Patenting the sun: Enclosing the scientific commons and transforming the university—ethical concerns.’’ [21]  ‘‘Medicinal chemistry: Through a glass darkly.’’ [22]  ‘‘Hijacked receptors.’’ [23]  ‘‘The sound of one hand clapping.’’ [24] David also has had real impact while serving in senior editorial roles at longstanding journals such as Drug Development Research. He gave educational presentations around the world, including what I understand were many visits to India (see Fig. 2 as one example). David’s insightful voice on industry and academia rang loud and clear in his days as editor of Pharmaceutical News, a valuable forum that I am sad to say no longer exists. In addition, I remember running into David from time to time at various symposia and Gordon Conferences, where his keen questions led to enlightening discussions and great, widely held respect for his intellect. In the 2000s, David served as an editor-in-chief of the eightvolume second edition of Comprehensive Medicinal Chemistry (CMC-II). This hard copy and online magnum opus, which I had the pleasure to be involved in, covered the state-of-the-art at the time of its printing, including volumes focused on the following: Global perspective Strategy and drug research Drug discovery technologies Computer-assisted drug design ADME-Tox approaches Therapeutic areas: central nervous system, pain, metabolic syndrome, urology, gastrointestinal and cardiovascular, cancer, infectious diseases, inflammation and immunology, and dermatology  Case histories      

David did more than just edit. He also contributed his academic perspective on a number of timely topics, including what he characterized as changing faces/places/directions, academia in a state of flux and a market environment, and scientific ethos and the globalization of science for richer and poorer worlds. Therein he [(Fig._2)TD$IG]strived to provide insights into:


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Benzothiazepine class: diltiazem shown

Dihydropyridine class: nifedipine shown


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Phenylalkylamine class: verapamil shown Fig. 1. Major structural classes of calcium channel blockers.

Fig. 2. Picture of (from left to right) Michael Walker, Walter Moos, and David Triggle, who led off the program at the 1st Indo-Japanese International Conference on Advances in Pharmaceutical Research and Technology. The meeting was held in Mumbai, India, on November 25–29, 2005. David served as the U.S. coordinator for the conference, presented an overview of drug discovery target selection, and chaired a session.


W.H. Moos / Biochemical Pharmacology 98 (2015) 360–362

 Addressing major pharmaceutical issues in an academic setting.  Training the next generation of medicinal chemists and pharmacologists.  Feedback from students and postdoctoral fellows after they experienced the ‘‘real world’’.  What university departments and pharma/biotech management might teach each other about cooperation.  A consultant’s viewpoint on industrial drug discovery.  The right (practical?) balance of innovative yet fundable research.  Dealing with tech transfer—as he put it, ‘‘caught between a university and a pharma place’’.  Technologies developed or in development at universities.  Scientific interfaces and boundaries including chemistry/biology.  Evolution of academic faculty and students in recent decades.  Perspectives of successful drug hunters in academia—before or after joining academia. For CMC-II, a major undertaking indeed, herding cats comes to mind in thinking about the individual volume editors, the many expert and opinionated chapter authors, and of course the publishers. Even in this day and age of Google, Twitter, and Wikipedia – the latest version of factoids and sound bites – I understand that a third edition of CMC is now being planned by the publisher and a few brave souls, yet one more example of the durability of David’s contributions to the foundations of science [25,26]. More recently, David has touched increasingly on the philosophy of science in his writings, especially integrity, and he has also opined further on the future of core scientific disciplines such as medicinal chemistry and pharmacology [27]. His pedagogy, wry smile, and honest chuckle will be remembered by all of us who have had a chance to get to know him. David, thank you for making so many worthwhile contributions to the biomedical sciences, and for your collegiality and thoughtprovoking discussions over the years. References [1] A.M. Triggle, E. Shefter, D.J. Triggle, Crystal structures of calcium channel antagonists: 2,6-dimethyl-3,5-dicarbomethoxy-4-[2-nitro-, 3-cyano-, 4-(dimethylamino)-, and 2,3,4,5,6-pentafluorophenyl]-1,4-dihydropyridine, J. Med. Chem. 23 (12) (1980) 1442–1445. [2] D. Rampe, D.J. Triggle, Benzodiazepines and calcium channel function, Trends Pharmacol. Sci. 7 (11) (1986) 461–464. [3] M. May, L. Czoncha, D.R. Garrison, D.J. Triggle, The analgesic, hypothermic, and depressant activities of some N-substituted a-5,9-dimethyl-6,7-benzomorphans, J. Pharm. Sci. 57 (5) (1968) 884–887,

[4] E.E. El-Fakahany, A.T. Eldefrawi, D.L. Murphy, L.G. Aguayo, D.J. Triggle, E.X. Albuquerque, M.E. Eldefrawi, Interactions of phencyclidine with crayfish muscle membranes. Sensitivity to calcium channel antagonists and other drugs, Mol. Pharmacol. 25 (3) (1984) 369–378. [5] J. Hampshire, P. Hebborn, A.M. Triggle, D.J. Triggle, S. Vickers, Potential folic acid antagonists I. The antitumor and folic acid reductase inhibitory properties of 6substituted 2,4-diamino5-arylazopyrimidines, J. Med. Chem. 8 (6) (1965) 745– 749. [6] D.J. Triggle, B. Belleau, Studies on the chemical basis for cholinomimetic and cholinolytic activity I. Synthesis and configuration of quaternary salts in the 1,3dioxolane and oxazoline series, Can. J. Chem. 40 (1962) 201–215. [7] N.B. Chapman, D.J. Triggle, Di-N-substituted 2-haloethylamines. VII. N,N-Dialkyl2-10 - or -20 -naphthyl derivatives, and some miscellaneous related compounds: synthesis, reactivity, and pharmacology, J. Chem. Soc. 4835 (1963) 41. [8] F.P. Field, R.A. Janis, D.J. Triggle, Aortic reactivity of rats with genetic and experimental renal hypertension, Can. J. Physiol. Pharmacol. 50 (11) (1972) 1072–1079. [9] M. Gopalakrishnan, D.J. Triggle, The regulation of receptors, ion channels, and G proteins in congestive heart failure, Cardiovasc. Drug Rev. 8 (3) (1990) 255–302. [10] J.F. Moran, V.C. Swamy, D.J. Triggle, Irreversible antagonism at the adrenergic areceptor. Role of calcium, Life Sci. 9 (22(Pt. 1)) (1970) 1303–1315. [11] M. May, B.J. Johnson, D.J. Triggle, J.F. Danielli, S.S. Gilani, The estrogenic activities of 16-alpha, 17-alpha- and 16-beta, 17-beta- epoxy-1,3,5(10)-estratriene-3-ol, Life Sci. (1965) 4705–4711. [12] D.J. Triggle, New aspects of estrogen action, Pharm. News 6 (1) (1999) 7. [13] C.R. Triggle, D.J. Triggle, Analysis of the action of cations of the lanthanide series on the mechanical responses of guinea-pig ileal longitudinal muscle, J. Physiol. 254 (1) (1976) 39–54. [14] V.C. Swamy, M. Ticku, C.R. Triggle, D.J. Triggle, The action of the ionophores, X537A and A-23187, on smooth muscle, Can. J. Physiol. Pharmacol. 53 (6) (1975) 1108–1114. [15] K.J. Chang, D.J. Triggle, Membranal Ca++ ion translocation and cholinergic receptor activation, in: M.A. Mehlman, R.W. Hanson (Eds.), The Role of Membranes in Metabolic Regulation, Proceedings of Symposium, Academic Press, New York, 1972, pp. 59–110. [16] R.A. Janis, D.J. Triggle, New developments in calcium ion channel antagonists, J. Med. Chem. 26 (6) (1983) 775–785, [17] D.J. Triggle, Nous Sommes Tous des Bacteries: implications for medicine, pharmacology and public health, Biochem. Pharmacol. 84 (12) (2012) 1543–1550. [18] D.J. Triggle, The chemist as astronaut: searching for biologically useful space in the chemical universe, Biochem. Pharmacol. 78 (3) (2009) 217–223. [19] D.J. Triggle, Treating desires not diseases: a pill for every ill and an ill for every pill? Drug Discov. Today 12 (3–4) (2007) 161–166. [20] D.J. Triggle, Everybody must get cloned: ideological objections do not hold up, Free Inquiry (Buffalo, NY) 23(1) (2002–2003) 32–3 [21] D.J. Triggle, Patenting the sun: enclosing the scientific commons and transforming the university-ethical concerns, Drug Dev. Res. 63 (3) (2004) 139–149. [22] D.J. Triggle, Medicinal chemistry: through a glass darkly, Annu. Rep. Med. Chem. 28 (1993) 343–350. [23] D.J. Triggle, Hijacked receptors, Pharm. Acta Helv. 74 (2–3) (2000) 287–290. [24] D.J. Triggle, The sound of one hand clapping, Pharm. News 6 (1) (1999), 4,6. [25] J.B. Taylor, D.J. Triggle (Eds.), Comprehensive Medicinal Chemistry II, 2nd ed., Elsevier, Oxford, UK, 2007. [26] W.H. Moos, The intersection of strategy and drug research, in: J.B. Taylor, D.J. Triggle (Eds.), 2nd ed., Comprehensive Medicinal Chemistry II, vol. 2, Elsevier, Oxford, UK, 2007, pp. 1–84. [27] C.R. Triggle, D.J. Triggle, What is the future of peer review? Why is there fraud in science?. Is plagiarism out of control?. Why do scientists do bad things? Is it all a case of: ‘‘all that is necessary for the triumph of evil is that good men do nothing’’?, Vasc. Health Risk Manage. 3 (1) (2007) 39–53.

A tribute to David Triggle.

"A gentleman and a scholar" is how many would characterize David Triggle. His insightful, thoughtful approaches to professional pursuits, both persona...
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