Synthesis and dopamine transporter affinity of chiral 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(2-hydroxypropyl)piperazines as potential cocaine abuse therapeutic agents.

A series of optically pure phenyl-and non-phenyl-substituted 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(2-hydroxypropyl)piperazines was synthesized and their binding affinity for dopamine transporter (DAT) was investigated. The analogues with a hydroxyl group in the S configuration were more selective for the DAT over the serotonin transporter (SERT) than the corresponding R enantiomers. Compound (+)-11 showed high affinity and selectivity for DAT over the SERT and, therefore, is a potential candidate for the development of a long-acting cocaine abuse therapeutic agent.

Synthesis and biological evaluation of 14-alkoxymorphinans. 17. Highly delta opioid receptor selective 14-alkoxy-substituted indolo- and benzofuromorphinans.

14-Alkoxy analogues of naltrindole and naltriben differently substituted in positions 5 and 17 and at the indole nitrogen (compounds 28-44) have been synthesized in an effort to enhance the delta potency and/or delta selectivity and in order to further elaborate on structure-activity relationships of this class of compounds. Introduction of a 14-alkoxy instead of the 14-hydroxy group present in naltrindole resulted in somewhat lower delta binding affinity, while in many cases (compounds 31, 34, 37, 40, 41, 44, HS 378) the delta receptor selectivity was considerably increased. An ethoxy group in position 14 is superior to other alkoxy groups concerning delta affinity and selectivity (34, 41, 42, 44, HS 378). In [35S]GTP gamma S binding, compounds 34, 41, and HS 378 exhibited about one-tenth the antagonist potency of naltrindole at delta opioid receptors while their delta antagonist selectivity was considerably higher. 17-Methyl-substituted compounds 35 and 44 were found to be pure delta receptor agonists in this test.