How does the chemical structure of a drug determine potency?

Question

I'm rather new to neuropharmacology, and I am particularly interested in why some psychotropic medications are more potent than others despite being in the same category of one another, (i.e.: Oxymorphone, and Etorphine being both opioids) and acting as agonists at the same receptors. I am aware that binding affinities determine the potency and strength of a drug. E.g.:

Morphine has an affinity of 1.8 nM (Ki) on the MORs. Whereas Fentanyl has a binding affinity of 0.39 nM (Ki) on the MORs. And so therefore, fentanyl requires a far lower dose than morphine for the patient receiving fentanyl to sustain adequate analgesia.

How are these two, totally structurally different opioids, able to agonise the same receptors, and how do the structures of them make one more potent than the other? A similar question goes for the following Drugs:

Why are most Triazolobenzodiazepines, such as: Clonazolam, Flunitrazolam, and Triazolam far more potent in their dose, and effects, then Benzodiazepines such as: Chlordiazepoxide, Nitrazepam, and Diazepam?

Why do small changes in the skeletal structure of psychoactive drugs have such a large impact on binding affinities?

Answer 1

In fact, the two binding affinities of fentanyl and morphine to the mu opiate receptors are considered to be fairly similar. The reason the former is the more potent one has more to due with its higher lipophilicity and therefore its better ability to cross the blood brain barrier. In addition, their internal cellular signaling pathways differ. This is caused by the two compounds binding to slightly different amino acid residues in the opiate binding pocket of the mu receptor (Fig. 1) (Lipiński et al., 2019).

Another thing to consider, besides pharmacodynamics, are the pharmacokinetics of different compounds. For instance, methamphetamine is way more potent than amphetamine, which in turn is way more potent that its parent molecule PEA. This is because the methyl groups block MAO from degrading the compounds (Shulgin & Shulgin, 1991). Pharmacokinetics may, or may not play a role in the morphine/fentanyl case as well.

<sub>References
- Lipiński et al., J Molec Mod (2019); 25: 144
- Shulgin & Shulhin, Pihkal, Transform Press, 1991</sub>

^{Fig. 1. Binding of fentanyl (a) and morphine (b) in the mu receptor binding pocket showing different amino acid residues in the receptor protein helices to be bonded causing differences in intracelllular signaling pathways to be activated. source: Lipiński et al. (2019)}