Comparing Compounds

Adjustments

Adjusting an active site may change a drug's effect.

Adjusting a non-active site may change the way a drug is digested, without changing its effect.

Immediate-acting antipsychotics are changed to long-acting injectable antipsychotics (second row) by adding a long-chain ester (decanoate, hexadeacanoate, or dodecanoate) to inactive sites. Note the difficulties of finding an appropriate attachment point: risperidone lacks the oxygen attachment: aripiprazole required an additional carbon and oxygen to be added to the molecule, suggesting that the oxygen in the short acting molecule is part of the active site.

Comparisons and Connections

Comparing multiple compounds that have a similar clinical response sometimes leads to clear similarities and differences:

shapes that are well-preserved suggest active binding sites
chemical differences without apparent clinical effect suggest inactive sites

Note that prazosin and terazosin have a 2,6 diaminopurine structure: like diaminopurine, they may inhibit adenosine deaminase: prazosin augments adenosine response 8187934

metoprolol, atenolol, propranolol, all beta-blockers, are compared against prazosin and terazosin, alpha-blockers, as well as carvedilol, which shares alpha and beta-blocker structure and function

Apparent Functional Groups and Naming

Comparing compounds with opposite clinical effects can be similarly helpful in correlating chemical structure to clinical action.

Naltrexone is an opiate blocker: comparing to common opiates suggests that the n-methyl group may be important for opiate function, while the 3-member ring (cyclopropane) may be important to the function of opiate blocker. Incidentally, naming conventions become more clear.

The importance of comparable orientation is also highlighted: to compare structures between drug classes, we will typically prioritize the phenyl ring and then orient similar to a purine's orientation. The nitrogen is similar to the guanine-defining nitrogen. The hydroxyl group in oxycodone and naltrexone helps the molecule more closely approximate a purine.

Another Ester Example

The same technique is used, but on a smaller scale, in ACE inhibitor design: enalapril prolongs the half-life by adding a two-carbon ester: PMID 2826067. The active metabolite is called enalaprilat and is given IV. IMG

Another Ester Example

Heroin adds two ester bonds to morphine, extending the half-life.

Other examples from opiates: fentanyl vs. carfentanyl

Val-prefix

Sometimes a valine group is added to a molecule in an ester bond: similar to ester bonds above, this prolongs the half-life of the molecule: e.g. valbenazine (daily)/tetrabenazine (TID) and valaciclovir/aciclovir.

Lis-prefix

Sometimes a lysine group is added to a molecule to create a prodrug: e.g. e.g. lisdexamfetamine. IMG

Another Ester

Gabapentin has alternative ester added to prolong half-life.

Electron Density

Although chemical structures accentuate the elements included (referring to the nucleus of the atoms), proteins, enzymes, and bonds all form on the basis of electrons. In general, N and O are opposites: O (and F/Cl/Br) tend to pull in electron density, whereas N will tend to push electron density away.

Consider amlodipine, where O pulls electron density away from adjacent structures, making them look like Ns: similar enough to cause Stevens-Johnson Syndrome: PMID 21772148, which we have associated with adenosine deaminase inhibition.

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