Synthesis and pharmacological investigation of novel 2-aminothiazole-privileged aporphines Original Research Article

A series of apomorphine ((−)-1, APO)-derived analogues ((±)-3, (−)-4-(−)-6) were designed and synthesized by hybridizing APO with a privileged 2-aminothiazole functionality which was lent from the orally available anti-parkinsonian drug, pramipexole (2). Among these hybridized compounds, catecholic aporphine (−)-6 shows good affinity at the D2 receptor with Ki of 328 nM, slightly less potent (3-fold), but more selective against the D1 receptor than that of the parent compound, APO. Although possessing reduced affinity at the D2 receptor, aporphines 15 and 18 show significant potency at both the D1 and 5-HT1A receptors. The former compound is equipotent at both receptors (Ki: 116 and 151 nM, respectively), while the latter is 8-fold more potent at the D1 (Ki: 78 nM) than at the 5-HT1A receptors (Ki: 640 nM). These results indicate that the catechol fragment is critical for the D2 receptor binding of the anti-parkinsonian drug, APO ((−)-1), but not necessary for binding at the D1 and 5-HT1A receptors.