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Oxazepam-Dopamine Conjugates Increase Dopamine Delivery into Striatum of Intact Rats.

Tommaso CassanoAntonio LopalcoModesto de CandiaValentino LaquintanaAngela LopedotaAnnalisa CutrignelliMara PerroneRosa M IacobazziGaurav BedseMassimo FrancoNunzio DenoraCosimo D Altomare
Published in: Molecular pharmaceutics (2017)
The neurotransmitter dopamine (DA) was covalently linked to oxazepam (OXA), a well-known positive allosteric modulator of γ-aminobutyric acid type-A (GABAA) receptor, through a carbamate linkage (4) or a succinic spacer (6). These conjugates were synthesized with the aim of improving the delivery of DA into the brain and enhancing GABAergic transmission, which may be useful for the long-term treatment of Parkinson disease (PD). Structure-based permeability properties, in vitro stability, and blood-brain barrier (BBB) permeability studies led to identify the OXA-DA carbamate conjugate 4a as the compound better combining sufficient stability and ability to cross BBB. Finally, in vivo microdialysis experiments in freely moving rats demonstrated that 4a (20 mg/kg, i.p.) significantly increases extracellular DA levels into striatum, with a peak (more than 15-fold increase over the baseline) at about 80 min after a single administration. The stability and delivery data proved that 4a may be a promising candidate for further pharmacological studies in animal models of PD.
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