Chronic neuroinflammation and cholinergic dysfunction are major contributors to cognitive decline in Alzheimer’s disease. Here, we report a series of pyridazine-based multitarget-directed ligands that simultaneously inhibit human butyrylcholinesterase (hBChE) and p38α mitogen-activated protein kinase (p38α MAPK). Pyridazines 8 and 21 were identified as potent dual inhibitors with submicromolar inhibitory potencies against target enzymes and high selectivity over acetylcholinesterase. X-ray crystallographic analyses revealed the experimental binding modes of 8 and 21 in hBChE and p38α MAPK, and identified conserved π–π, π–cation, and hinge region interactions that rationalize dual-target engagement. Both compounds were blood-brain barrier permeable, exhibited low cytotoxicity, and significantly attenuated lipopolysaccharide-induced proinflammatory responses and apoptosis in BV2 microglia. In vivo, compound 21 enhanced cognitive performance in mouse models of scopolamine-induced amnesia and LPS-stimulated neuroinflammatory cognitive impairment. Collectively, these results document the potential of structure-assisted design to achieve selective dual-target pharmacology within a single molecular entity.

Beyond the well-established roles of serotonin and calcitonin gene-related peptide (CGRP), the contribution of dopamine (DA) to migraine pathophysiology remains a subject of intense investigation. DA acts as a neuromodulator, functioning both as a homeostatic pain filter and a driver of premonitory and autonomic symptoms. This review provides a comprehensive synthesis of DA’s involvement in migraine, proposing an integrated model that spans from molecular signaling to a systemic phenotype. A comprehensive search of the PubMed database (1976–2026) was performed. The analysis evaluates data across receptor signaling, hypothalamic connectivity (specifically the A11 nucleus), genetic susceptibility markers and advanced neuroimaging studies. Current evidence identifies dopamine as a gatekeeper of the trigeminovascular threshold, with the hypothalamic A11 nucleus serving as a modulatory hub. Within this circuit, DA exerts concentration-dependent effects: high-affinity D2 receptor activation promotes antinociception, whereas low-affinity D1-like receptors facilitate nociceptive signaling. Clinically, this manifests as a “dopaminergic phenotype” characterized by yawning, nausea, and reward-system dysfunction. This phenotype extends beyond migraine, showing links to comorbidities such as restless legs syndrome (RLS) and attention-deficit/hyperactivity disorder (ADHD). DA’s role in migraine is state-dependent and interconnected with CGRP and serotonergic pathways. Recognizing the dopaminergic phenotype is essential for capturing the clinical heterogeneity of the disorder and may pave the way for personalized, mechanism-based therapeutic strategies.