“…The molecule of histamine has been extensively modified (Figure 3), including substituents on the imidazole C atoms (A) 41,42 , replacing the imidazole ring with other heterocycles, such as 2,4,6-trisubstituted pyridinium (B), 1,3,4-thiadiazole (C) or a combination of these two ring systems (D) 43,44 and functionalising the NH 2 group, as in carboxamides/ureas/thioureas (E) 45 , sulphonamides (F) 46 , arylsulfonylureas (G) 47 , bis-histamine (H) 48,49 , oligopeptides 49,50 , or imidazole/imidazoline derivatives of the alkaloyd spinaceamine 51,52 and drug clonidine 53 (Figure 3) were reported to possess improved CA activatory profile when potency and isoform selectivity are concerned. Interestingly, pharmacological agents born for other medical applications (Figure 4) showed also to possess more or less relevant CA-activating effects, among which psychoactive compounds of the amphetamine and methamphetamine family 54 , the selective serotonin reuptake inhibitors fluoxetine, sertraline and citalopram 55 , the phosphodiesterase IV inhibitor sildenafil 56 , and the b-blocker amino alcohol derivative timolol 57 . Timolol was taken as lead compound in the present study to design a new series of uncommon CAAs, which do not bear imidazole like scaffolds, intesively explored in the field.…”