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.