Rational Design of Photochromic Analogues of Tricyclic Drugs

Abstract

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 mimic the tricyclic chemical structure and display reversibly controlled activity. 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.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.

Rational Design in Photopharmacology with Molecular Photoswitches

“…Atypical tricyclic azosteres were explored very recently for the first time, during the development of photoswitchable antagonists of M 1 mAChR. [152] The design stemmed from a ligand-based hypothesis, i.e., the shape similarity between (Z)-azobenzene and the fused tricyclic scaffold of pirenzepine. Such hidden bioisosteric replacement was termed "crypto-azologization", because a bond needed to be broken to carve the (Z)-like azostere out of the scaffold (Figure 20).…”

Molecular Switches—Tools for Imparting Control in Drug Delivery Systems

“…In all cases discussed to this point, a conformational change of the molecular switch is used to release a drug payload by distorting the structure of its carrier. An attractive, atypical approach to minimise toxicity and focus the APIs potency to the tumorous site is to incorporate the photochromic mechanism into the structure of the therapeutic API itself, thus mimicking the drug with a photochromic agent ( Riefolo et al, 2021 ). A method employed by Sheldon et al was to use the core of an azobenzene to engineer a photochromic analogue of combretastatin A-4 (CA4) ( Sheldon et al, 2016 ).…”

Recent Advancements in Ion‐Pair Receptors

“…Noticeably, changes in the molecular structure, alters the physical property such as fluorescence, electrical conductivity, refractive index, polarizability, and magnetism etc [41] . In recent years, these type of appealing molecules has gained a prominent attention of the scientific community globally because of their unique physiochemical signatures and diverse potential applications for instance, photo‐responsive self‐assemblies, [42] information manipulation, [43] medicinal chemistry, [44] logic gates, [45] molecular switches, [46] and fluorescent chemosensors [47] etc. Remarkably, in recent past, a plethora of photochromic systems have successfully been designed, synthesized and studied worldwide by numerous research groups.…”