Thiophene analogs of naphthoxazines and 2-aminotetralins: bioisosteres with improved relative oral bioavailability, as compared to 5-OH-DPAT

In the present study, a series of thiophene analogs of 2-aminotetralins and hexahydronaphthoxazines were studied in vivo for their ability to decrease striatal dopamine release, their effects on locomotor activity, and their behavioral characteristics in reserpinized rats, in order to investigate wh ether a thiophene moiety can act as a bioisostere for the phenol moiety. In general, the new compounds showed lower in vivo activities than 5-hydroxy- 2-(N, N,-di-n-propylamino)tetralin (5-OH-DPAT). However, the introduction o f the thiophene moiety gave a significant improvement of the relative oral bioavailability, compared to 5-OH-DPAT. Our results suggest that the thioph ene moiety can act as a bioisostere for a phenol group in hydroxylated 2-am inotetralins. For the thianaphthoxazines it was not possible to discriminat e between bioisosterism for a phenyl or a phenol moiety. The tetrahydrobenz o[b]thiophenes could be used as lead compounds for the development of novel dopamine receptor ligands with improved relative oral bioavailability. (C) 2000 Elsevier Science B.V. All rights reserved.