title: Synthesis of 4-substituted nipecotic acid derivatives and their evaluation as potential GABA uptake inhibitors.
abstract: In this study, we disclose the design and synthesis of novel 4-susbtituted nipecotic acid derivatives as inhibitors of the GABA transporter mGAT1. Based on molecular modeling studies the compounds are assumed to adopt a binding pose similar to that of the potent mGAT1 inhibitor nipecotic acid. As substitution in 4-position should not cause an energetically unfavorable orientation of nipecotic acid as it is the case for N-substituted derivatives this is expected to lead to highly potent binders. For the synthesis of novel 4-substituted nipecotic acid derivatives a linear synthetic strategy was employed. As a key step, palladium catalyzed cross coupling reactions were used to attach the required biaryl moieties to the ω-position of the alkenyl- or alkynyl spacers of varying length in the 4-position of the nipecotic acid scaffold. The resulting amino acids were characterized with respect to their binding affinities and inhibitory potencies at mGAT1. Though the biological activities found were generally insignificant to poor, two compounds, one of which possesses a reasonable binding affinity for mGAT1, rac-57, the other a notable inhibitory potency at mGAT4, rac-84, both displaying a slight subtype selectivity for the individual transporters, could be identified.
authors.affiliation: Department of Pharmacy-Center for Drug Research, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377 Munich, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Hellenbrand
authors.affiliation: Department of Pharmacy-Center for Drug Research, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377 Munich, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Höfner
authors.affiliation: Department of Pharmacy-Center for Drug Research, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377 Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wein
authors.affiliation: Department of Pharmacy-Center for Drug Research, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377 Munich, Germany. Electronic address: klaus.wanner@cup.uni-muenchen.de.
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Wanner
mesh_terms: D004353:Drug Evaluation, Preclinical; D058805:GABA Uptake Inhibitors / Q000494:pharmacology*; D009557:Nipecotic Acids / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D058805:GABA Uptake Inhibitors; D009557:Nipecotic Acids; C030278:nipecotic acid
keywords: Biological evaluation; GABA uptake; Nipecotic acid; Suzuki–Miyaura reaction; mGAT1