pA₂ = negative log (molar conc.) of antagonist that produces a two-fold agonist shift; higher pA₂ ⇒ higher antagonist affinity/potency at that receptor.

Schild plot (log[antagonist] vs log(CR−1)): slope ≈ 1 /-1 to support competitive reversible property; x-intercept = pA₂.

Receptors flip between resting (R) and active (R*) on their own.

If, at equilibrium, a small fraction sits in R*, you’ll see a basal activity.

Basal activity = the receptor’s own built-in signal when no agonist is present.

Inverse agonist: binds the same orthosteric site but prefers the resting (R) state --> reducing basal signal

pKᵢ = binding affinity (higher pKᵢ → tighter binding)

But clinical choice ≠ affinity alone. Consider:

1. Selectivity (e.g., M1 vs M2 vs M3) to hit the right receptor and avoid off-target AEs.

2. Route & PK (absorption, first-pass, metabolism, half-life; quaternary vs tertiary amines → CNS penetration).

3. Disease location & delivery (local vs systemic: inhaled for airways, topical for eye, oral for bladder).

4. Safety & patient factors (comorbidities like glaucoma/BPH, age/cognition, DDIs).