Discovery of bridged melanostatin derivatives as potent allosteric modulators of the dopamine D2 receptors with improved permeability.
Discovery of bridged melanostatin derivatives as potent allosteric modulators of the dopamine D2 receptors with improved permeability.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Porto, PT · Author affiliation
LAQV/REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto 4169-007, Portugal. Electronic address: ivdias@fc.up.pt.Location evidence
Bari, IT · Author affiliation
Department of Pharmacy - Pharmaceutical Sciences, University of Bari "Aldo Moro", Via E. Orabona 4, Bari 70125, Italy.Location evidence
Santiago de Compostela, ES · Author affiliation
Innopharma Screening Platform, Biofarma Research Group, Centre of Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, Santiago de Compostela E-15782, Spain.Location evidence
Matosinhos, PT · Author affiliation
Interdisciplinary Centre of Marine and Environmental Research (CIIMAR/CIMAR), University of Porto, Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/n, Matosinhos 4450-208, Portugal.Location evidence
A Coruña, ES · Author affiliation
Department of Chemistry-CICA, University of A Coruña, Campus da Zapateira, s/n, A Coruña 15008, Spain.Location evidence
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Original abstract
Melanostatin (MIF-1) is an endogenous positive allosteric modulator (PAM) of dopamine D2 receptors (D2R) with recognized therapeutic potential in central nervous system (CNS) disorders associated with dopaminergic dysfunction, particularly Parkinson's disease. However, the therapeutic development of MIF-1 has been limited by poor pharmacokinetic properties. Building on previous studies of conformationally constrained MIF-1 analogs, the present work describes the design, synthesis, and comprehensive functional, toxicological, and permeability evaluation of new bridged derivatives incorporating the enantiopure scaffold (1R,3S,4S)-2-azanorbornane-3-carboxylic acid as a hybrid prolyl/pipecolyl surrogate. The target MIF-1 derivatives were synthesized through a concise and stereoselective route, and their absolute configuration was unequivocally established by X-ray crystallography. Pharmacological assays at human D2R identified four active derivatives (7b, 8d, 9c, and 9d) that potentiated dopamine responses by 5.3- to 6.6-fold at concentrations as low as 10 pM, consistent with PAM-like activity. Toxicological profiling in HepG2 (100 µM) and differentiated SH-SY5Y neuronal cells (up to 200 µM) confirmed that these compounds are well tolerated at supra-pharmacological concentrations, except for 9c. Additionally, these compounds exhibited reduced P-gp-mediated efflux and improved Caco-2 permeability compared to MIF-1. Overall, these findings identify 2-azanorbornane as a promising scaffold for the development of D2R PAM ligands with favorable pharmacokinetic and safety profiles.