Microsoft word - answers_ch08.doc

Essentials of Medicinal Chemistry, CHM 310 Patrick, An Introduction to Medicinal Chemistry 4e Answers to end-of-chapter questions
1) The three molecules are very similar to each other. Structures I and II differ from acetylcholine in having an amino group and an ethyl group respectively instead of a One might expect structure II to be active since a methyl and ethyl group are more similar to each other than an amino group. Both are hydrophobic groups that can interact by van der Waals interactions. In contrast, the amino group is a polar group that is more likely to interact by hydrogen bonding. The fact that structure I is active and structure II is inactive suggests that it is not binding that is crucial here and that the difference in activity is due to the sizes of the different groups. The methyl and amino groups are similar in size, whereas the ethyl group is larger. If the space available in the binding site is limited, structure II may not fit due to the larger ethyl group. Further details can be found in sections 22.7-22.9. 2) The inactive metabolite has a methyl ether rather than a phenol group. This indicates that the phenol group is an important binding group when isoprenaline interacts with the adrenergic receptor. For example, the hydrogen atom of the phenol group may act as a hydrogen bond donor to a crroesponding hydrogen bond acceptor in the binding site. This interaction is no longer possible for the inactive metabolite. Another possibility is that the phenolic oxygen acts as a hydrogen bond acceptor and that the methyl group in the metabolite prevents this interaction due to its size and bulk (see also sections 14.2.6 and 23.10.3). 3) This question is related to question 4 above. Larger and bulkier N-alkyl groups result in selectivity for the β-receptors (see also section 23.10.3) 4) Both molecules contain the identical moiety shown in red. Oxford University Press, 2009. All rights reserved. Essentials of Medicinal Chemistry, CHM 310 Patrick, An Introduction to Medicinal Chemistry 4e The carbon bearing the alcohol group is an asymmetric centre has the same configuration in each molecule. This is demonstrated by redrawing propranolol as Therefore, it is possible for this moiety in both molecules to form similar interactions with the receptor. However, the aromatic systems are different and so different interactions are possible here, which can account for propranolol acting as an antagonist rather than as an agonist if a different induced fit results. Propranolol is likely to show β-adrenergic selectivity due to the fact that it has a bulky N-alkyl substituent (compare questions 4 and 6, see also section 23.11.3.1) 6) It is worth considering the interactions of oestradiol and raloxifene with the oestrogen receptor (box 8.2) in order to answer this question. Both oestradiol and raloxifene contain functional groups that can interact through hydrogen bonding to the amino acids Glu-353, Arg-394 and His-524. Both molecule have hydrophobic skeletons that position these groups correctly and match the hydrophobic nature of the binding site. Oestradiol is an agonist whereas raloxifene is Oxford University Press, 2009. All rights reserved. Essentials of Medicinal Chemistry, CHM 310 Patrick, An Introduction to Medicinal Chemistry 4e an antagonist. This is due to the extra interaction with Asp-351 that is possible for raloxifene. Turning now to tamoxifen, this molecule is also hydrophobic and of a similar size to the above, allowing it to fit the hydrophoic binding site. It does not have the phenol or alcohol functional groups present in oestradiol or raloxifene, but it does have a group that can interact with Asp-351 in the same way as raloxifene, resulting in it acting as 7) Although tamoxifen itself is an antagonist, its metabolite is an agonist. This is because it has lost the group that is so crucial for antagonist activity (the side chain containing the amine). It also contains a phenol group which can mimic the phenolic Oxford University Press, 2009. All rights reserved.

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