John 5. Wishnok
Boston University Boston, Mossochusetts 02215
Medicinal Properties of Adamantane Derivatives
Adamantane (I) has interested chemists for over 40 years (I), and research hased on its unusual chemical and physical properties has led to important advances in several areas of organic chemistry including structure-reactivity relationships ( 2 ) ,carbon hyperconjugation (3), and degenerate rearrangements of nominally stable molecules (4). In the early 1960's an entirely new aspect of adamantane research was revealed with the discovery that l-aminoadamantane (11) had potent inhibitory properties against several types of viruses, especially influenza viruses (5) hut also a number of other types such as rubella virus (6) and fowl tumor viruses (7). The discovery of this interesting hiological property of l-aminoadamantane stimulated a large number of investigations in which structurally related compounds were assaved for hioloeical activitv. Most of these comnounds did hut none of the simple amines exkhit antiviril directlv analoeous to l-aminoadamantane showed notably greate; potency than 1-aminoadamantane itself. Only recently has an antiviral agent significantly more effective than l-aminoadamantane been developed within this general class of compounds. This molecule, N-methyladamantanespiro-3'-pyrrolidene (111) is up to three times more active than l-aminoadamantane, and is also effective against a broader spectrum of viruses (8).
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The medicinal applications of the polycyclic hydrocarbon amines as antiviral agents are, in some respects, unique, since their effects are specific against certain strains of viruses, and their action does not involve the classic vaccination orocess in which an oreanism is treated with a relatively impotent form of a disease-causing aeent and is then stimulated to woduce s~ecificantih;dies against the infectious agents: Instead, i-aminoadamantane is more effective as a preventive agent when it is administered prior to infection, and its action continues only until it has been metaholized or eliminated (9). Further, and despite its virus specificity, the initial hiological interaction of l-aminoadamantane appears to be with host cells rather than with the virus. It does not destroy the V ~ N S nor even seriously diminish its potency and, apparently, does not even prevent attack of the cell by the virus. Recent evidence, in fact, seems to indicate that the virus attack can progress as far as the actual penetration of the membrane of the affected cell (10). The subsequent steps in the process of viral replication, however, are prevented and no serious infection occurs. Although the potential uses of l-aminoadamantane as an antiviral aeent aonear to he hiehlv snecialized. it is probably true ;hat thk'real hiologicariipokanee of adamantane derivatives lies more in their versatility than in their effectiveness in treating or preventing a single type of disease. Adamantane derivatives or adamantyl-containing members of medicinal homologs-in addition to antiviral behavior-have shown biological activity as sedatives (111, antitumor agents (IY), hypoglycemic agents ( I antiarrythmtc agents (141, anridepressive agents (15). and in [rearing the symptoms uf Parkinson's disease 780 / Journal of Chemical Education
(16). From observations such as these, it is clear that an adamantyl group confers additional potency on drugs in which i t is oresent. and research into the causes of this effect should yield powerful insights into the principles of drue desim and the nature of the biological interactions thatresult in medicinal hehavior for organic molecules. One property that has been cited in several investigations is the lipophilicity of the adamantyl group. A major constituent of hiological membranes is the non-polar hydrocarbon portion of the long-chain fatty acids in phospholipids. An increase in the lipophilicity (i.e., solubility in non-polar media), therefore, often increases the ease with which a compound reaches the site of activity. An early example of this type of effect was found in the N-arylsulfonyl-N'-alkyl ureas, which are well known for their ability to reduce the level of hlood sugar, and are useful in the treatment of diabetes. (Compounds which have this property of lowering hlood sugar levels are known as hypoglycemic agents.) Compound (IV), with adamantyl as the alkyl group, has been found to be a potent hypoglycemic agent (3). Although the lipophilicity of the adamantyl group was among the major factors which dictated its choice as a favorable modification of the basic drug structure in the case of the arylsulfonyl alkyl ureas, the final results indicated that the lipophilicity of the compound, while important, was not the only property which determined the potency of the drug. Most other structural modifications of the adamantyl derivatives lowered the activity of the compound (13). This can he interpreted as suggesting that a specific steric factor is important in the crucial interaction at the site of activity, i.e., lipophilic properties aid the molecule in reaching the site of activity hut do not necessarily increase the effectiveness of the molecule at that site. This reasoning suggests that the only types of drug behavior which would be related solely to lipophilicity would be those in which the biological properties depended simply on the presence of the drug at the site of activity. This type of hehavior has often been associated with compounds such as anesthetics (17) or narcotics (IS), and attempts to correlate narcotic effects with lipophilicity have been moderately successful (18, 19). At least one investigation has been explicitly based on the lipophilic properties of adamantane derivatives. Compound (V), l-adamantylcarhoximide, and a variety of methylated derivatives, have been evaluated for sedative properties. In these experiments, increasing methyl substitution clearly increased the sedative potency, and this was attributed to the increasing ease with which the molecules reached the central nervous system (11). The important therapeutic effects of l-aminoadamantane in alleviating the symptoms of Parkinson's disease, a disorder of the central nervous system, are probahly also related to the lipophilicity of the adamantyl group (16). The effects of l-aminoadamantane are in some respects similar to those of L-DOPA, so l-aminoadamantane can
also be used to test for the potential usefulness of LDOPA. This is an important function since response to 1aminoadamantane appears to taper off, and increased doses produce undesirable side effects (16). As mentioned earlier, lipophilicity can be of major importance in assisting a drug to reach the site of biological action. Once at that site, however, a number of other properties may become important, with the total effect involving additional well-defined drug-receptor interactions. For example, if the biological interaction involves inhibition of an enzyme, the net effect may reflect the strength with which the drug binds to an active site on the enzyme as well as the ahility of the drug to alter some property of the enzyme such as its conformation. These concepts have been strikingly demonstrated for a series of alkyl substituted diamino pyrimidines (VI-VIII), which are important as potential anticancer drugs.
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observations have led to encouraging results in experiments with other types of cancer cells which are resistant to amethopterin because of inefficient uptake of the drug (20). As a final point, i t is interesting to note that the idea which has just been described-that the lipophilicity of the adamantyl group can often be utilized to increase the effectiveness of drug molecules to which it is attachedhas led to a large and growing number of examples in which this appears to be a valid principle of drug design. A recent investigation however, in which the biological activity of l-aminoadamantane was compared with that of the somewhat analogous structures (IX) and (X), has led to results which suggest that the major factor in determining the antiviral activity of this class of compounds is t h e p K of the nitrogen rather than its lipophilicity (21). It is thus apparent that the biological interactions of adamantane derivatives are much more complex than might be expected on the basis of their structure. These molecules are clearly among the simplest of organic medicinal compounds, but it is equally clear that this simplicity is deceptive. Literature Cited (1) Lands, S., C k m . Lisly, 2'7,415 l19331:27.44311933). (2) Gleicher, G. J.. and S c h l e y e ~P. von R., J. Amor C h m Soc.. 89, 582 (19671: Fort, R. C., and Schloyer. P. von R., Chem Rau, 64, 277 (19641, and reference3 in both artidea. (3) Bingham, R.C., andSehleyer,P.vonR.,J Am-. Chem. Soc., 93,318911971~. (4) Malerski, Z., Liggem, S. H.. and Sehlcyer, P, "on R.. Chem Commun., 1596
Several compounds in this class have been investigated (12) in terms of their in oioo ability to inhibit the growth of tumor cells and in terms of their ability to inhibit the in oitro action of dihydrofolate reductase, an enzyme which is important in DNA biosynthesis. The mechanism of tumor inhibition in this case is thought to involve dihydrofolate reductase inhibition. In these experiments, enzyme inhibition constants were determined directly in simple in uitro systems. The inhibition of tumor cell growth by a given compound, then, was assumed to be a function of both the enzyme inhibition constant of that compound and the speed-with which the com~oundreached the location in the cell where it encounterid the enzyme. The enzyme inhibition potency of compound (VDI) was found to he only 0.01 as great as that for a known dihydrofolate reductase inhibitor, amethopterin. The ability of compound (VIII) to inhibit tumor cells, however, was essentially the same as that for amethopterin, and this was interpreted as reflecting the ease with which the adamantane derivative could reach the active site. These
119701 ,....,. ( 5 ) Davios. W. L.. Gwnort, R. R., Half, R. F.. MeGshen, J. W., Neumayer. E. M.. Paulshoek, N.. Waf*. J. C.. Wmd. T. R.. Herman". E. C., and Hoffman, C. E.,
Scimez, 144,862 11964). (6) Cachran. K. W., and Maasssb, H. F., Fed. Roe. Fed. Amel Sor. Erp. B i d 23. 387 (15%). I71 Oker-Rlom, N., and Anderson. A.L., Eur. J Conrrr, 2,911968). (81 Lundahl. K., Schut, J.. Schlatmann. J. L. M. A,, Paerels. G. B.. and Peters. A., Eur J. Conrer, 15, 129l19721. (91 Hoffman, C. E.. Neumayer. E. M.. Haff, R. F.. and Goldsby, R. A , J B o c f d o L 90.623 11965). (10) Ksta N.. and Eggem, H., V k l o g y . 37,612 (19691. (11) Goram. K., Tohiss, D. J., sr., Holmes, R. E.. Rathbun. R. E.. and Ksttau, R. W., J. Med. Chem., 10, W3 11967). 112) Ho. Y. K.. Hakala, M. T.. and Zakrzeaaki. S. F.. Cancer Resooreh. 32. 1023 ,>m,m \.*,-,.
(13) Geman. K., Krumkalus, E. V.. Brindle, R. L., Manhsll. F. J.. and Raot. M. A . J. Med. Cham.. 6.760 119611. (14) Nsryanan. V.L., andSweenoy, F. J.. J. M e d Chem 15.143 (1972). (15) Nsryanan, V. L.. J. Med. Chem 15.682 119721. (16) Schwab, R. S., Englsnd, A. C.. Pakanrcr. D. C.. and Young, R. R.. J. Amer. Med. Assoc., 208, 1168(1969). (17) Korolkauas, A . "Essential8 ot Moleeulsr Phsrmaeolo~."Wilcy-Inferscience, New York 1970, pp. 8. 9,13-21. andlefereneor cited. (18) Hsnsch. C., "Dmg Design." Vol. I. (Editor Ariends. E. J.1. Academic Pres, NCW
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(191 Hansch, C.,Arcfs. Chem. Re&, 2.232(1969). (201 Nichol. C.A.,Advonc. Enlym~Regulolron,6.305(19681. (211 G~unewald,G. L.. Warner, A.M., Hays, S. J., Russell, R. H., and Seals. M. K.. J. Med. Chem.. 15.747(1972).
Volume 50, Number 7 1 , November 1973
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