The present work reports the synthesis of enantiomeric pairs of the trans-2-amino-6-hydroxyl-phenyl-2,3-dihydro-1H-indene [(+)-14a, (-)-14a] and trans-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] derivatives obtained by a combination of stereospecific reactions and optical resolution. The new compounds were evaluated for their affinity at the dopamine D-1 and D-2 receptors. The amines (+)- and (-)-14a, incorporating the D-1 pharmacophore 2-phenyl-2-(3-hydroxyphenyl)ethylamine in a trans extended conformation, and their derivatives displayed D-1 and D-2 affinity in the nanomolar range. On the other hand, the enantiomers (+)- and (-)-14b, (+)- and (-)-15b displayed high affinity and selectvity for the D-1 receptor. In a preliminary behavioral study on rats (+)-14b, and to a greater extent (+)-15b, promoted episodes of intense grooming, thus indicating that they act as central D-1 agonists. The trans-2-amino-5-hydroxy-1-phenyl-2,3-dihydro-1H-indenes (+)-14b and (+)-15b represent selective D-1 agonists lacking a catechol group, which should meet the prerequisites for a central nervous system penetration.
Synthesis, resolution, and preliminary evaluation of trans-2-amino-6(5)-hydroxy-1-phenyl-2,3-dihydro-1H-indenes and related derivatives as dopamine receptors ligands / F., Claudi; Gm, Cingolani; A., Distefano; G., Giorgioni; F., Amenta; P., Barili; Ferrari, Francesca; Giuliani, Daniela. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - STAMPA. - 39:(1996), pp. 4238-4246.