Orally Active and Potent Inhibitors of γ-Aminobutyric Acid Uptake

Ali, Fadia E.; Bondinell, William E.; Dandridge, P. A.; Frazee, James S.; Garvey, E.; Girard, G. R.; Kaiser, Carl; Ku, Thomas W.; Lafferty, John J.; Moonsammy, George I.; Oh, Hye-Ja; Rush, Julia A.; Setler, Paulette E.; Stringer, Orum D.; Venslavsky, Joseph W.; Volpe, Beth W.; Yunger, Libby M.; Zirkle, Charles L.

doi:10.1021/jm50001a020

Cited by 146 publications

(90 citation statements)

References 11 publications

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“…42 Nipecotic acid (NIP) is a GABA reuptake inhibitor with great therapeutic potential if it would be able to cross the BBB. [43][44][45] GABA is the primary inhibitory neurotransmitter in the CNS, and decreased levels of this molecule are associated with several brain disorders. The levels of this amino acid in the CNS can be increased either by supplying GABA or its agonists, or via GABA reuptake inhibitors, such as NIP.…”

Section: Transport Ability Of (Phpro) 4 Shuttle Using the Pampa Assaymentioning

confidence: 99%

Lipid Bilayer Crossing—The Gate of Symmetry. Water-Soluble Phenylproline-Based Blood-Brain Barrier Shuttles

et al. 2015

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Drug delivery to the brain can be achieved by various means, including blood-brain barrier (BBB) disruption, neurosurgical-based approaches, and molecular design. Recently, passive diffusion BBB shuttles have been developed to transport low-molecular-weight drug candidates to the brain which would not be able to cross unaided. The low water solubility of these BBB shuttles has, however, prevented them from becoming a mainstream tool to deliver cargos across membranes. Here, we describe the design, synthesis, physicochemical characterization, and BBB-transport properties of phenylproline tetrapeptides, (PhPro)4, an improved class of BBB shuttles that operates via passive diffusion. These PhPro-based BBB shuttles showed 3 orders of magnitude improvement in water solubility compared to the gold-standard (N-MePhe)4, while retaining very high transport values. Transport capacity was confirmed when two therapeutically relevant cargos, nipecotic acid and l-3,4-dihydroxyphenylalanine (i.e., l-DOPA), were attached to the shuttle. Additionally, we used the unique chiral and conformationally restricted character of the (PhPro)4 shuttle to probe its chiral interactions with the lipid bilayer of the BBB. We studied the transport properties of 16 (PhPro)4 stereoisomers using the parallel artificial membrane permeability assay and looked at differences in secondary structure. Most stereoisomers displayed excellent transport values, yet this study also revealed pairs of enantiomers with high enantiomeric discrimination and different secondary structure, where one enantiomer maintained its high transport values while the other had significantly lower values, thereby confirming that stereochemistry plays a significant role in passive diffusion. This could open the door to the design of chiral and membrane-specific shuttles with potential applications in cell labeling and oncology.

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Section: Transport Ability Of (Phpro) 4 Shuttle Using the Pampa Assaymentioning

confidence: 99%

Lipid Bilayer Crossing—The Gate of Symmetry. Water-Soluble Phenylproline-Based Blood-Brain Barrier Shuttles

et al. 2015

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“…Although both compounds show in vitro high GABA uptake inhibition without intrinsic activity at GABA A -receptors, the pharmacological usefulness of these compounds was limited as they lack the capability to cross the bloodebrain barrier [24]. This obstacle was overcome by introducing characteristic lipophilic side chains to the parent compounds like nipecotic acid and guvacine leading to several GABA uptake inhibitors such as SK&F-89976-A [25] (4, Fig. 2), Tiagabine [26] (5, Fig.…”

Section: Introductionmentioning

confidence: 99%

Development of imidazole alkanoic acids as mGAT3 selective GABA uptake inhibitors

Hack

Wörlein

Höfner

et al. 2011

European Journal of Medicinal Chemistry

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“…The reuptake inhibitor SKF 100330A may have a more specific effect. This drug has been shown to have pharmacological effects suggesting strong activation of GABAergic systems (Löscher 1985;Zorn et al 1985) while having no or slight effect on other neurotransmitters (Yunger et al 1984;Ali et al 1985).…”

Section: Discussionmentioning

confidence: 99%

GABAergic drugs and sexual motivation, receptivity and exploratory behaviors in the female rat

Ågmo

Soria

1997

Psychopharmacology

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Female rats were allowed to pace sexual interactions in a bilevel chamber, where a sexually vigorous male was tethered to the bottom level. Exploratory behaviors (sniffing, rearing), locomotor activity (expressed as number of level changes and periods of inactivity) as well as items of sexual motivation (latency to descend to the male's level, approaches towards the male and genital exploration) were recorded. In addition, sexual receptivity was evaluated in a non-paced situation. A test for motor impairment was also performed. The GABA transaminase inhibitor gamma-acetylene GABA reduced exploratory behaviors at doses much lower than those needed to reduce receptivity. The GABA reuptake inhibitor SKF 100330A did not affect any behavior category at doses of 15 and 30 mg/kg, but had a sedative action at 60 mg/kg. This was shown as impaired motor coordination and an almost total absence of activity in the bilevel chamber. Receptivity was not impaired, however. The mixed GABAA/ GABAB agonist progabide reduced exploratory behaviors and receptivity without producing motor impairment at a dose of 400 mg/kg. The GABAA agonist THIP impaired motor coordination and reduced receptivity and exploratory behaviors at a dose of 10 mg/kg. A larger dose, 20 mg/kg, had a strong sedative action. Only a small proportion of the animals descended to the males level. The GABAB agonist baclofen reduced receptivity at a dose that had no effect on motor coordination or exploratory behaviors. None of the drugs had a specific effect on sexual motivation. Whenever behaviors reflecting motivation were reduced, there were also other behavioral effects indicative of sedation. These data show that GABA receptor agonists, particularly the GABAB agonist baclofen, reduce sexual receptivity at doses that have only slight effect on motor functions or exploratory behaviors. In contrast, non-specific enhancement of GABAergic activity by a transaminase or reuptake inhibitor have effects on motor functions and exploratory behaviors at doses much lower than those needed to reduce receptivity.

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Orally Active and Potent Inhibitors of γ-Aminobutyric Acid Uptake

Cited by 146 publications

References 11 publications

Lipid Bilayer Crossing—The Gate of Symmetry. Water-Soluble Phenylproline-Based Blood-Brain Barrier Shuttles

Lipid Bilayer Crossing—The Gate of Symmetry. Water-Soluble Phenylproline-Based Blood-Brain Barrier Shuttles

Development of imidazole alkanoic acids as mGAT3 selective GABA uptake inhibitors

GABAergic drugs and sexual motivation, receptivity and exploratory behaviors in the female rat

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