Question

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3. (5 pts) Suggest whether the following structures B-F are likely to act as cholinergic agonists or not and describe your rationale. If it will act as an agonist, compare its expected activity to acetylcholine (structure A) A forma overk oyna o cork lone wykona

Answer 1

Solution: A cholinergic agents are those that mimics the activities of compounds such as acetylcholine (structure A). “Choline” in general, means any quaternary ammonium salts with N,N,N-trialkylethanolammonium cation. Here, methyl group is preferred as alkyl. CH3 _ N,N,N- trimethylethanolammnium cation. Hzc __ OH CH3 The structure of acetylcholine is written as, CH3 CH3 CH3 H3C Now, if a molecule has to satisfy cholinergic conditions then it should possess the following relationships, 1. The molecule must contain a N-atom with a positive charge. Any quaternary ammonium salt is preferred. 2. In order to obtain maximum efficiency, the alkyl groups on the N-atom should not be more than methyl group. 3. It should have an O-atom (preferably ester) which can participate in hydrogen bonding. 4. Between N-atom (from salt) and O-atom (from ester), there should be a two-carbon unit present in the middle.

5. There must be two methyl groups present in the quaternary salt. Another bulky alkyl group can be there but presence of more than one makes it less reactive. 6. Bigger the overall molecule size, poorer is the activity. Considering all these conditions, we can say that structure B-F are likely to act as cholinergic agoinsts. The activity can be approximated as follows, E<D<C<B< F Structure E is the most least reactive because of the presence of two bulky alkyl groups on the quaternary salt portion. CH3 CH₃ Hąc Structure D is second least reactive because of the presence of one bulky alkyl group on the quaternary salt portion. СН3 CH₃ Hąc

Structure C is third least reactive because of the presence N linkage). Because N is less electronegative atom compared to C-atom, the H-bond forming will be less strong and hence the reactivity. CH3 СН3 CH3 Hąc Structure B is second most reactive because of it has all the structural characteristics present similar to acetylcholine only instead it has propionyl group in place of acetyl group. CH3 CH₃ H3C -CH₃ Structure F is most reactive because of it has all the structural characteristics present similar to acetylcholine. Besides, the -NH2 group in the side chain can resonate with -C=O group which makes the O-atom from the ester linkage more electron rich. This helps more in better H-bonding. CH3 CH3 -ch3 HN