Synthesis and pharmacological investigation of novel 2-aminothiazole-privileged aporphines

Abstract

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 D 2 receptor with K i of 328 nM, slightly less potent (3-fold), but more selective against the D 1 receptor than that of the parent compound, APO. Although possessing reduced affinity at the D 2 receptor, aporphines 15 and 18 show significant potency at both the D 1 and 5-HT 1A receptors. The former compound is equipotent at both receptors ( K i: 116 and 151 nM, respectively), while the latter is 8-fold more potent at the D 1 ( K i: 78 nM) than at the 5-HT 1A receptors ( K i: 640 nM). These results indicate that the catechol fragment is critical for the D 2 receptor binding of the anti-parkinsonian drug, APO ((−)- 1), but not necessary for binding at the D 1 and 5-HT 1A receptors.