Benzodiazepines have been exhaustively applied for the development of ligands for the large family of GABA(A) receptors (Sigel et al. 2018). In addition, the benzodiazepine scaffold has been used to develop ligands for GPCRs. Examples are the development of CCK receptor ligands (Evans et al. 1989) and recently the development of vasopressin V2 receptor antagonist (Cao et al. 2022).
Our group has reported the evaluation of imidazobenzodiazepines with the support of the Psychoactive Drug Screening Program (PDSP) and confirmed that many of these compounds bind the κ opioid receptor (KOR) in addition to the GABA(A) receptors (Li et al. 2020). The most potent compound GL-I-53 had Ki of 27 nM for KOR and recruited G-protein αo with an EC50 value of 32 nM. Thus, GL-I-53 is a full KOR agonist with a six-fold selectivity over GABA(A) receptor expressed in the rat brain.
Secondly, we recently identified benzodiazepine MF-1-78 with the ability to bind alpha adrenergic receptors with a 7.7-fold selectivity for α2B over the α2A subtype and a weak selectivity α2B over the α2C subtype (2.2-fold) (Fernando et al. 2025). The affinity for adrenergic receptor α2A is 511 nM with a twofold selectivity over rat brain GABA(A) receptors. MF-1-78 is an α2A antagonist preventing the recruitment of beta arrestin to the activated receptor.