For several years the ‘one-molecule, one-target’ paradigm dominated scientific research, and drug development was concentrated on single drugs that are highly potent and selective for specific biological targets.(p1) Undoubtedly, this approach led to the development of numerous drugs, but in complex diseases like neurodegenerative syndromes and autoimmune disorders, the existing single-target therapy struggles to provide satisfying long-term therapeutic effects.(p2),(p3)

Dual ligands offer several advantages over one-target molecule, especially in complex therapeutic contexts. A dual ligand can modulate two signaling pathways, simultaneously addressing multiple aspects of a pathology and offering a more comprehensive therapeutic approach. A ligand that activates two different receptors can often produce a synergistic effect, reducing the need to administer multiple drugs and consequently reducing the side effects associated with multiple treatments. In addition, the use of a dual-target ligand could lower the risk of developing drug resistance, as the biological system would need to simultaneously adapt to the inhibition of two distinct molecular targets rather than just one.(p4),(p5),(p6)

In recent years, dual-target drugs gained increasing attention, emerging as a promising strategy for treating complex diseases. This trend that has also been reflected in the number of dual drugs approved by the FDA.(p7),(p8)

Purinergic receptors are widely recognized for their therapeutic involvement in several pathological conditions, and dual agents targeting purinergic receptors have shown considerable promise in preclinical studies for the treatment of neurodegenerative diseases, rheumatoid arthritis, ischemia, and cancer. Purinergic receptors are divided into two main families: P1 receptors, which are activated by adenosine and AMP, and P2 receptors, stimulated by purine nucleotides such as ATP, ADP.(p9) P1 receptors are coupled to G proteins and are classified as four receptor subtypes: A1, A2A, A2B, and A3. Among these, A2A adenosine receptors (A2AARs) are involved in several pathologies especially in the pathophysiological processes of Parkinson’s disease (PD). In fact, A2AARs are coupled to dopamine D2 receptors: antagonists of A2AARs allow greater interaction of dopamine with its own D2 receptors, improving the activity of the dopaminergic system, which is severely compromised in PD.(p10),(p11) Furthermore, in recent years, the possible involvement of these receptors in antitumor therapies has become increasingly clear.(p12) This perspective describes how further development of compounds with antagonistic activity toward adenosine receptors could lead to new candidates in this sector.

The big family of P2 receptors is divided into two subfamilies: the P2X receptor (P2XR) and P2Y receptor (P2YR). Whereas P2XRs are channel receptors, P2YRs are coupled to G proteins. Numerous receptor subtypes have been identified within the two large subfamilies and variously classified; these are generally ubiquitous in the body, each with distinct tissue distributions and physiopathological roles. Among these, the P2X1R is involved in HIV-1 infection, and its inhibition blocks the fusion of the viral membrane on the cell surface, preventing viral infection.(p13)

The P2X7R plays a pivotal role in the neuroinflammation associated with neurodegenerative diseases.(p14) In light of the foregoing, the use of ligands able to inhibit the P2X7R and glutamatergic N-methyl-D-aspartate (NMDA) receptors, which are chronically overstimulated during neurodegenerative diseases, could represent a good therapeutic approach.(p15),(p16),(p17),(p18),(p19) Similarly, P2Y2Rs represent a therapeutic strategic target in neuroinflammation activating cellular responses under the proinflammatory conditions associated with neurodegenerative diseases such as Alzheimer’s disease (AD) and participating in the regulation of neuroprotective responses.(p20),(p21),(p22),(p23) Furthermore, the P2Y2R signaling pathway seems to be involved in neuronal regeneration and angiogenesis during spinal cord injury (SCI).(p24) The anti-inflammatory and neuronal regeneration effects could be enhanced by GPR17 inhibition, which would counteract cerebral ischemic injury progression by regulating neuronal death and microglial activation.(p25)

P2Y12Rs, unlike others P2YR subtypes, have a limited tissue distribution, playing a primary role in platelet aggregation.(p26) Thus P2Y12R antagonists are widely used as antiplatelet agents in cardiovascular disorders. Their therapeutic potential could be enhanced when combined with inhibition of thromboxane A2 receptors, which contribute to platelet aggregation and vascular smooth muscle contraction.(p27) Currently, even if there are some indirect and functional interactions between these two systems that are worth considering, there is no strong evidence that P2Y12R antagonists can directly inhibit the production or activity of thromboxane A2.

In this review, we provide an overview of the most promising dual ligands, which are able to interact with purinergic receptors and other G-protein-coupled receptors or enzymes, endowing them with therapeutic potential for the treatment of diseases.