Structural Activity Relationship

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Chapter: Medicinal Chemistry : Cholinergic Drugs

Acetylcholine can exist in a number of conformations. Four of these conformations are synplanar, synclinal, anticlinal, and antiplanar.


STRUCTURE ACTIVITY RELATIONSHIP

  • Acetylcholine can exist in a number of conformations. Four of these conformations are synplanar, synclinal, anticlinal, and antiplanar.

  • The most active isomer is the (+) trans enantiomer and it is identical to synclinal conformation of acetylcholine.

  • The muscarinic receptors and acetylcholinesterase display stereoselectivity, the (S) enantiomer of methacholine is equipotent with acetylcholine, while the R (–) enantiomer is about 20-fold less potent.



I. Modification of Quaternary Ammonium Group

  • The quaternary ammonium group is essential for intrinsic activity, and contributes to the affinity of the molecule for the receptors, partially through the binding energy and partially because of its action as a detecting group.

  • The trimethyl ammonium group is the optimal functional moiety for the activity, although some exceptions are known (e.g. pilocarpine, nicotine, and oxotremorine), and it shows maximal muscarinic activity.

  • Placement of primary, secondary, or tertiary amines leads to decrease in activity.


II. Modification of acyloxy group

  • The ester group of ACh contributes to the binding of the compound to the muscarinic receptor.

  • Replacement of methyl group by ethyl or large alkyl groups produces inactive compounds.

  • Esters of aromatic or higher molecular weight acids possess cholinergic antagonist activity.


III. Modification of ethylene bridge

  • The methyl ester is rapidly hydrolyzed by cholinesterase to choline and acetic acid. To reduce susceptibility to hydrolysis, carbamate esters of choline (carbachol) were synthesized and were found to be more stable than carboxylate esters.

  • Placement of α-substitution in choline moiety results in a reduction of both nicotinic and muscarinic activity, but muscarinic activity to a greater extent.

  • Incorporation of β-substitution leads to reduction of nicotinic activity to greater extent.

  • Replacement of ester group with ether or ketone produces chemically stable and potent compounds.

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