Rational Design of Photochromic Analogues of Tricyclic Drugs

Tricyclic chemical structures are
the core of many important drugs
targeting all neurotransmitter pathways. These medicines enable effective
therapies to treat from peptic ulcer disease to psychiatric disorders.
However, when administered systemically, they cause serious adverse
effects that limit their use. To obtain localized and on-demand pharmacological
action using light, we have designed photoisomerizable ligands based
on azobenzene that mimic the tricyclic chemical structure and display
reversibly controlled activity. Pseudo-analogues of the tricyclic
antagonist pirenzepine demonstrate that this is an effective strategy
in muscarinic acetylcholine receptors, showing stronger inhibition
upon illumination both in vitro and in cardiac atria ex vivo. Despite the applied chemical modifications to make
pirenzepine derivatives sensitive to light stimuli, the most potent
candidate of the set, cryptozepine-2, maintained a moderate
but promising M1 vs M2 subtype selectivity.
These photoswitchable “crypto-azologs” of tricyclic
drugs might open a general way to spatiotemporally target their therapeutic
action while reducing their systemic toxicity and adverse effects.