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Oxazepam–Dopamine Conjugates Increase Dopamine Delivery into Striatum of Intact Rats

2017; American Chemical Society; Volume: 14; Issue: 9 Linguagem: Inglês

10.1021/acs.molpharmaceut.7b00405

1543-8392

Tommaso Cassano, Antonio Lopalco, Modesto de Candia, Valentino Laquintana, Angela Lopedota, Annalisa Cutrignelli, Mara Perrone, Rosa Maria Iacobazzi, Gaurav Bedse, Massimo Franco, Nunzio Denora, Cosimo Altomare,

Neurotransmitter Receptor Influence on Behavior

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.