Rational design of photochromic analogs 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. In order to obtain localized and on-demand pharmacological action using light, we have designed photoisomerizable ligands based on azobenzene that mimics the tricyclic chemical structure and displays reversibly controlled activity. Several pseudo analogs 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. 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.