The Case of Anti Dopaminergic 6Methoxysa IicyIamides

In the course of studying the physico-chemical and structural properties of antidopa-minergic 6-methoxysalicylamides [32, 33], the compound raclopride was shown by us to exist in water at pH 7.4 as a zwitterion with stereoelectronic features completely different from those of other classes of dopamine antagonists such as orthopramides. Using first-derivative UV spectroscopy, the uncharged rather than zwitterionic form of raclopride was found to partition predominantly into the octanol phase. Using the CPC method, we established its pH-lipophilicity profile in the two solvent systems octanol/water and heptane/water [33]. Furthermore, the very low Alog /JC)C1_a|k value of raclopride (0.5) indicates the existence of strong internal hydrogen bonds (OH...O=C and CH30... HNC=0) in biological lipophilic media. A simplified scheme showing the interconversion, predominance, and conformational behavior of neutral and zwitterionic raclopride in a biphasic system is presented in Fig. 9. These results thus help in revealing the true pharmacophoric features of 6-methoxysalicylamides which are therefore stereoelectronically similar to those of other orthopramides.

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