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 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 mimic tricyclic structure display reversibly controlled activity. Pseudo-analogues antagonist pirenzepine demonstrate this is an strategy in muscarinic acetylcholine receptors, showing stronger inhibition upon illumination both vitro cardiac atria ex vivo. Despite applied modifications make derivatives sensitive light stimuli, most potent candidate set, cryptozepine-2, maintained a moderate but promising M1 vs M2 subtype selectivity. photoswitchable crypto-azologs might open general way spatiotemporally target therapeutic while reducing systemic toxicity effects.