Comparative Anti-Inflammatory Profile of Some Cytisine and Tetrahydroisoquinoline Derivatives: Interactions with COX-2 and Histamine H1 Receptors

Accumulating evidence indicates extensive crosstalk between prostaglandin- and histamine-mediated signaling pathways. Histamine has been shown to induce COX-2 (Cyclooxygenase-2) expression and stimulate prostaglandin synthesis, whereas prostaglandins potentiate the vascular and inflammatory effects of histamine, creating a positive feedback loop that sustains inflammation. Based on these considerations, in silico molecular docking study of interaction of new cytisine and TGIQ (tetrahydroisoquinoline) derivatives with COX-2 and the histamine H1 receptor was performed. Among the synthesized compounds, compound 1 exhibited the highest binding affinity toward Cyclooxygenase-2 (COX-2). Within the binding pocket of the human H1 histamine receptor, the binding affinity profile differed markedly from that observed for COX-2, with compound 4 exhibiting the highest therapeutic potential and the strongest binding affinity, surpassing all reference compounds. The high anti-inflammatory efficacy of the studied compounds was confirmed in formalin- and histamine rat models. THIQ derivatives were shown to possess a higher anti-inflammatory index than cytisine derivatives. Comparative evaluation of the anti-inflammatory activity of isoquinoline and quinolizidine derivatives revealed that the isoquinoline derivatives possess marked anti-inflammatory properties combined with low toxicity, making them promising candidates for the development of novel, highly effective and safe anti-inflammatory agents for both oral and topical administration.