Structural motives of imidazoline molecules favouring the serotonin 5-HT1A receptor activation

For several years our studies have been engaged in the design and preparation of biologically active ligands directed to different biological systems and characterized by a common scaffold bearing the 2-substituted imidazoline nucleus. We have demonstrated that minor chemical modifications in the bridge (X) determine preferential or multitarget recognition, whereas those in the aromatic moiety are generally responsible for the ligand functional behaviour. Among the most interesting compounds, we point out the nicotinic agonist homoazanicotine, the pheripheral monoamino oxydase A inhibitor amifuraline, the selective I1-imdazoline receptor agonist and antihypertensive agent carbomethyline, the selective I2 imidazoline binding sites ligand phenyzoline, the preferential α2C adrenergic agonist, also endowed with analgesic activity, biphenyline, and the very interesting α2C-AR agonists/α2A-AR antagonists allyphenyline and cyclomethyline. These latter enhance morphine analgesia at low dose (0.05 mg/Kg), preventing and reversing morphine tolerance and dependence without sedative side effects. Such beneficial effects prove to be associated to significant antidepressant effect at the same low dose. Experiments carried out in the presence of the α2-AR antagonist yohimbine and the serotonin 5-HT1A-receptor (5-HT1A-R) antagonist WAY100135 suggest that not only α2C but also 5-HT1A activation is involved in the antidepressant-like activity. In addition, at the same low dose, allyphenyline reduces hyperanxiety-like behaviour after alcohol intoxication. Therefore, for the first time we have showed that ligands bearing the 2-substituted imidazoline nucleus as a structural motif are also suitable to interact with 5-HT1A-R. With the aim to report further ligands targeting such a receptor and highlight the structural characteristics of our pharmacophore favouring the 5-HT1A interaction and activation we examined the in vitro 5-HT1A profile of a large number of imidazoline molecules prepared by us over the years. Some novel ligands have also been included in this study. Confirming the versatility of the 2-substituted imidazoline nucleus, the obtained results also suggest that the bridge, bearing a polar function and an additional methyl group, and the aromatic moiety, bearing an ortho substituent of suitable steric hindrance, positively affect the 5-HT1A-R recognition and activation. In addition, both the size and shape of the ortho substituent also appear to govern the behaviour of the chiral compounds. All the aforementioned evidences are further proved by docking and molecular dynamics carried out on a model built by comparative building based on the 5-HT1B receptor X-ray data. Interestingly, and as expected, this investigation has allowed to highlight some potential multifunctional agents able to reduce neuropatic pain, opiate withdrawal syndrome and psychiatric comorbidities.