Novel l-prolyl-l-leucylglycinamide (PLG) tripeptidomimetics based on a 2-azanorbornane scaffold as positive allosteric modulators of the D2R.
An efficient and straightforward orthogonal methodology was successfully developed to achieve constrained l-prolyl-l-leucylglycinamide (PLG) analogues starting from two proline mimetics based on a 2-azanorbornane scaffold. A preliminary dopamine D2receptor radiolabeled binding assay with [3H]-N-propylnorapomorphine shows that enantiopurity of PLG peptidomimetics based on 2-azanorbornane is a requirement to achieve statistically significant positive modulators of the D2receptor. This is the first documented active peptidomimetic of PLG whose bioactivity is not correlated with the C-terminal carboxamide pharmacophore and which cannot adopt the hypothesized type II β-turn conformation.
UCIBIO/REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal. idias@fc.up.pt jrborges@fc.up.pt.
Ivo E
http://orcid.org/0000-0002-9071-6197
IE
Sampaio-Dias
LAQV/REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal.
Carlos A D
http://orcid.org/0000-0002-1124-2860
CA
Sousa
Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, E-15782 Santiago de Compostela, Spain.
Xerardo
X
García-Mera
Instituto de Química, Universidade Federal da Bahia, Campus de Ondina, Salvador-BA, 40170-290 Brazil.
Joana
J
Ferreira da Costa
Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, E-15782 Santiago de Compostela, Spain.
Olga
O
Caamaño
UCIBIO/REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal. idias@fc.up.pt jrborges@fc.up.pt.
José E
JE
Rodríguez-Borges
D000494:Allosteric Regulation / Q000187:drug effects; D015195:Drug Design; D009075:MSH Release-Inhibiting Hormone / Q000737:chemistry*; D009636:Norbornanes / Q000737:chemistry*; D057786:Peptidomimetics / Q000737:chemistry* / Q000494:pharmacology*; D017448:Receptors, Dopamine D2 / Q000737:chemistry / Q000378:metabolism*
D009636:Norbornanes; D057786:Peptidomimetics; D017448:Receptors, Dopamine D2; D009075:MSH Release-Inhibiting Hormone