Impact of Structural Differences on thein VitroGlucuronidation Kinetics of Potentially Dopaminergic Hydroxy‐2‐Aminotetralins and Naphthoxazines Using Rat and Human Liver Microsomes

The in vitro glucuronidation of seven monohydroxy-2-aminotetralins and two naphthoxazines has been determined using human and rat liver microsomes. All these compounds stimulate the D2 dopamine receptor. The influence of the position of the phenolic hydroxyl group was studied with rat microsomes in monohydroxy-2-(N,N-dipropylamino)-tretralins. The highest activity and intrinsic clearance was found for 7-OH-DPAT, but the latter values for 5-OH-DPAT and 6-OH-DPAT were much lower by a factor of 9 and 30, respectively. The 8-OH-isomer was not glucuronidated at all. Substitution of a propyl side chain by a thienylethyl-, or phenylethyl side chain, in 5-hydroxy-DPAT, or in (+)-4-propyl-9-hydroxyhexahydronaphthoxazine (PHNO, N-0500), showed a large increase of the UDPGT affinity and intrinsic clearance especially for N-0437. It also resulted for N-0437 in a much higher affinity towards the dopaminergic D2 receptor. Although the glucuronidation activity of human microsomes was found to be considerably lower than that of rat microsomes, the latter phenomenon was clearly visible with human microsomes as well. These findings may have serious implications for the ability of these drugs to adequately reach the brain.