SYNTHESIS, RESOLUTION, AND PRELIMINARY EVALUATION OF AMINO-6(5)-HYDROXY-1-PHENYL-2,3-DIHYDRO-1H-INDENES AND RELATED DERIVATIVES AS DOPAMINE-RECEPTORS LIGANDS

The present work reports the synthesis of enantiomeric pairs of the ns -2-amino-6-hydroxyl-phenyl-2,3-dihydro-1H-indene [(+)-14a, (-)-14a] an d s-2-amino-5-hydroxy-1-phenyl-2,3-dihydro-1H-indene [(+)-14b, (-)-14b ] and their N,N-di-n-propyl [(+)- and (-)-15a,b], N-methyl-N-allyl [()- and (-)-16a,b], and N-methyl-N-n-propyl [(+) and (-)-17a,b] derivat ives obtained by a combination of stereospecific reactions and optical resolution. The new compounds were evaluated for their affinity at th e dopamine D-1 and D-2 receptors. The amines (+)- and (-)-14a, incorpo rating the D-1 pharmacophore 2-phenyl-2-(3-hydroxyphenyl)ethylamine in a trans extended conformation, and their derivatives displayed D-1 an d D-2 affinity in the nanomolar range. On the other hand, the enantiom ers (+)- and (-)-14b, (+)- and (-)-15b displayed high affinity and sel ectvity for the D-1 receptor. In a preliminary behavioral study on rat s (+)-14b, and to a greater extent (+)-15b, promoted episodes of inten se grooming, thus indicating that they act as central D-1 agonists. Th e -2-amino-5-hydroxy-1-phenyl-2,3-dihydro-1H-indenes (+)-14b and (+)-1 5b represent selective D-1 agonists lacking a catechol group, which sh ould meet the prerequisites for a central nervous system penetration.