Medicinal Chemistry/Pharmacology in Sophomore Organic Chemistry -
Allne M. H a n i m York College of Pennsylvania, York. PA 17403 Traditionally, the content of sophomore organic chemistry has included preparations, reactions, and mechanisms of the reactions of basic organic chemical functional groups, followed by "special topics". If one peruses current, widely used texts, options for such topics include rearrangements, specialty reactions such as the Diels-Alder or additions to a,&unsaturated carhonyl compounds, molecular orbitals and orbital symmetry, Hammett equation considerations, photochemistry, organometallics, or heterocycles. T o the svnthetic oreanic chemist these t o ~ i c sare indeed soecial. ~" but to an outsider many are merely specialized categorizations of earlier information.. . oresented in s e a t e r detail. In any event, such isolation of organic chemistry from application in other disciplines may be useful or even necessary in curricula where a selection of advanced courses is availahle, hut for the smaller colleges with limited advanced offerings, inclusion of some topics of wider applicability may serve students better. I have developed a series of lectures in medicinal chemistrylpharmacology for use a t the end of the second semester of the traditional sequence. The lectures have been carefully designed to illustrate the use of general organic chemical principles in molecular biology, to open doors of current research in interdisciplinary areas t o the beginner. to increase interest in organic chemistry as a dynamic, evolutionary enterprise, and to bridge the gap between traditional organic chemistry, biology, and the consumer. The risks associated with adopting this subject matter are (1) that the material presented in a given year will probably need to be modified the next year because information is accumulating quite rapidly, (2) that students will find popular reading includes articles in these areas and that thev mav even occasionally come to class with information tde instructor has not seen yet! and (3) that areas related to the emerging field of psychoneuroimmunology ("psychoneuroimmunochemistry!") are highly controversial. Praises be that an organic chemist should ever he in the pnsition of defending his (her) stance to a novice! The traditional part of the course concludes after treatment of all the basic functional groups as well as fats, carhohydrates, and proteins (Morrison and Boyd, Organic Chemistry, 5th ed.). The medicinal chemistrylpharmacology section is then nresented. For this unit. the students receive a complete set of lecture notes (revised annually as necessary), and additional current readings are olaced on reserve a t the library. Their receipt of lecture notes is not unusual, because I alsodistribute lecture notes for the rest of the course (1.2) though they are in less detail due to the availability of the text. For this section overhead transparencies duplicating the lecture notes (3)are used because ;,f the detailed nature of the notes and my desire to emphasize particular items. An outline of the material is shown below.-(A copy of student notes is availahle upon request.) ~~
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Definitionsofgeneral terminology and nomenclatureofdrugcontents, bioavailabilicy, clinical effecriveness, br,ertirrty, etc.--definition and principles
Theories of drug activity, specific and nonspecific including spatial and chemical requirements for receptor interactions. 3. Quantitative aspects of drug-receptor interactions-equilihriumlmass actions orincioles. 4. Quanta1and graded dose responses-graphical analysis, l.l)w. EDc,, therapeutic ratio. ew. 5. Examples of the use of receptor theory in modern drug design 2.
(4,5). 6. The route by which drugs come to the market (6). I . Synthesis of drugs-a comparison of the modification of a pro-
totype for opioid pain killers-(modifications of morphine, attention to agonists, antagonists,etc.) with a wide-areasearch for cancer ehemotheraoeutin. 8. Penicillin antibiotics-molecular modification. 9. Goals in the synthesis of new drugs and current innovations for their accomplishment (7). 10. "The immune system, a s p d application of receptor theory"an overview of the immune system and how it functions through principles of receptor interaction. 11. Biochemical connections of the central nervous (CNS) and immune systems (8,9). 12. "Naturalligands" (endorphins)and the potential for theirnatural induction (the placebo effect and other milieux), stressinduced analgesia (10). Epllogue As an introduction t o medicinal chemistry, I tell the story of the discovery of lihrium as detailed by the 1978 ACS Medicinal Chemistry Award winner Leo Sternhach in his award acceptance speech (11). Because the information in these lectures is drawn from a laree and ever-increasina number of sources, the notes are wec referenced to the current literature. The area of opioid synthesis was oriainally chosen as a contrast to the s-ynthesis of cancer chemotherapeutirs, because there is a remarkable difference of approach between them due to thedifferences in rhemical and pharmacological information available in each area. In addition, most people experience pain and/or cancer either personally or through a loved one a t some time during their lives. Thus, the material is also useful as eeneral information. As an indication of the evolutionary nature of these topics, I would note that the basic areas (Items 1-4 and 6-8) were developed some 10 years ago (predated hy isolated topics as long as 20 years ago). At the outset, the cancer and morphine topics were treated independently and then related through contrasting principles of drug "design". As the other enumerated topics have been added and the originals modified, more information is bringing the areas together. In fact, with recent findines on the aooarent role of endomhins as immunomodulahs (12,13) and the role of the immune system in the etiolow of cancer (14).the tooics are mereine into one interrelatedwiackage that iiiustrates the applicatron of organic chemical principles to human biological function.
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Acknowledament The author is grateful t o E. A. Harrison, Jr., for comments on this manuscript and on the material described, parts of which he has alsotaught over the last several years t o classes a t the Penn StateNork Campus. Volume 66 Number 10 October 1989
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Literature Cited 1. Harriaon, E.A,, Jr.: Harriaon. A. M. J. Chom. Edue. 1975.52.654, 2. Harrison, E. A. In Directory of Teaching Innouoliow in Chemistry; Meeth, L. R.; Gregori. D. S.. Eda; American Chemiurl Society & Studies in Higher Education: Washington, DC, 1981;pp 369-370. 3. Harrison. A. M. I" Directory of Teaching I n n o v o f i o ~in Chemistry; Meefh, L. R.; Gregoy, D. S., Eds;American Chemical Saeiety & Studies in Higher Education: Washington. DC, 1981:pp 131-132. 4. Kolata. G. Science 1987.235.11%&1139. 5. Hesp, B. Sympasium: The Lineor P o t h w y of Arochidanic Arid Metobollam Oppar *unities for Drug Design. ACS Middle Atlantic Regional Meeting: Millersville, PA, 1988.
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6. Spangler, C. W. Organic Chamisfry: A B&f Contemparory Perapodiw: PmntieeHall: Endewmd Cliffs. NJ. L980.
