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Synthesis and Biological Characterization of (3 R ,4 R )‐4‐(2‐(Benzhydryloxy)ethyl)‐1‐(( R )‐2‐hydroxy‐2‐phenylethyl)‐piperidin‐3‐ol and Its Stereoisomers for Activity toward Monoamine Transporters
Author(s) -
Kharkar Prashant S.,
Batman Angela M.,
Zhen Juan,
Beardsley Patrick M.,
Reith Maarten E. A.,
Dutta Aloke K.
Publication year - 2009
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200900085
Subject(s) - dopamine transporter , piperidine , chemistry , stereochemistry , serotonin transporter , norepinephrine transporter , dopamine , transporter , potency , serotonin , monoamine neurotransmitter , receptor , in vitro , biochemistry , biology , endocrinology , gene
A novel series of optically active molecules based on a 4‐(2‐(benzhydryloxy)ethyl)‐1‐(( R )‐2‐hydroxy‐2‐phenylethyl)‐piperidin‐3‐ol template were developed. Depending on stereochemistry, the compounds exhibit various degrees of affinity for three dopamine, serotonin, and norepinephrine transporters. These molecules have the potential for treating several neurological disorders such as drug abuse, depression, and attention deficit hyperactivity disorder.Herein we describe the synthesis and biological evaluation of a series of asymmetric 4‐(2‐(benzhydryloxy)ethyl)‐1‐(( R )‐2‐hydroxy‐2‐phenylethyl)‐piperidin‐3‐ol‐based dihydroxy compounds in which the hydroxy groups are located on both the piperidine ring and the N ‐phenylethyl side chain. In vitro uptake inhibition data of these molecules indicate high affinity for the dopamine transporter (DAT) in addition to moderate to high affinity for the norepinephrine transporter (NET). Interestingly, compounds 9 b and 9 d exhibit affinities for all three monoamine transporters, with highest potency at DAT and NET, and moderate potency at the serotonin transporter (SERT) ( K i : 2.29, 78.4, and 155 n M for 9 b and 1.55, 14.1, and 259 n M for 9 d , respectively). Selected compounds 9 a , 9 d , and 9 d′ were tested for their locomotor activity effects in mice and for their ability to occasion the cocaine‐discriminative stimulus in rats. These test compounds generally exhibit a much longer duration of action than cocaine for elevating locomotor activity, and completely generalize the cocaine‐discriminative stimulus in a dose‐dependent manner.