5. Concluding remarks
Alcohol use disorders remains a major socioeconomic burden, and treatment novel options remain elusive. Several orphaned neuropeptides and oGPCRs are expressed throughout key reward circuitry (Figure 2) and may provide novel targets and treatments for AUD; however, limitations remain. Despite considerable efforts in the field of GPCR de-orphanisation, more than 100 receptors remain orphaned, and these receptors are also disproportionally understudied (Alexander et al., 2023; Roth & Kroeze, 2015). The challenges with orphaned peptides and receptors persist, including technical - limited availability of sensitive screening assays or ability to test appropriate ligands and biological - a possible lack of endogenous ligand or receptor. In some instances, these may have become evolutionarily redundant, or receptors may only signal through ligand independent mechanisms (e.g. constitutive activity or dimerisation) (Fricker & Devi, 2018; Tao & Conn, 2014). With the development of integrated computational, structural, functional and experimental approaches, elucidating orphan peptide and orphan receptor interactions through screening putative receptors/ ligands in silico are promising areas of future research (Foster et al., 2019). Further, advancements in cryo-EM have enhanced exploration into membrane bound GPCRs in both active and inactive state confirmations and artificial intelligence approaches, such as machine learning are increasing efficiency in drug design and development (Casadó & Casadó-Anguera, 2023), including several GPCR targeting compounds that have progressed to phase I/II clinical trials (e.g. EXS21546, a selective A2A receptor antagonist for renal cell carcinoma - clinicaltrials.gov ID: NCT04727138 & NCT05920408). We have outlined several targets that should be further explored as potential treatment options for AUD; however, limitations in small molecule compounds and mechanistic understanding are currently halting development. Leveraging emerging technologies will both enhance our fundamental understanding of orphaned peptides and receptors and provide a more rapid and precise method to identify pharmacotherapies to provide more treatment options for AUD.