TY - JOUR
T1 - The Significance of Chirality in Drug Design and Synthesis of Bitopic Ligands as D3 Receptor (D3R) Selective Agonists
AU - Battiti, Francisco O.
AU - Cemaj, Sophie L.
AU - Guerrero, Adrian M.
AU - Shaik, Anver Basha
AU - Lam, Jenny
AU - Rais, Rana
AU - Slusher, Barbara S.
AU - Deschamps, Jeffery R.
AU - Imler, Greg H.
AU - Newman, Amy Hauck
AU - Bonifazi, Alessandro
N1 - Funding Information:
This project was supported by National Institute on Drug Abuse—Intramural Research Program ZIA DA 000609. The authors thank Dr. Ludovic Muller from the Structural Biology Core at NIDA-IRP for high-resolution MS analyses. The X-ray crystallographic work was supported by NIDA through Interagency Agreement #Y1-DA1101 with the Naval Research Laboratory (NRL).
Publisher Copyright:
© 2019 American Chemical Society.
PY - 2019/6/19
Y1 - 2019/6/19
N2 - Because of the large degree of homology among dopamine D2-like receptors, discovering ligands capable of discriminating between the D2, D3, and D4 receptor subtypes remains a significant challenge. Previous work has exemplified the use of bitopic ligands as a powerful strategy in achieving subtype selectivity for agonists and antagonists alike. Inspired by the potential for chemical modification of the D3 preferential agonists (+)-PD128,907 (1) and PF592,379 (2), we synthesized bitopic structures to further improve their D3R selectivity. We found that the (2S,5S) conformation of scaffold 2 resulted in a privileged architecture with increased affinity and selectivity for the D3R. In addition, a cyclopropyl moiety incorporated into the linker and full resolution of the chiral centers resulted in lead compound 53 and eutomer 53a that demonstrate significantly higher D3R binding selectivities than the reference compounds. Moreover, the favorable metabolic stability in rat liver microsomes supports future studies in in vivo models of dopamine system dysregulation.
AB - Because of the large degree of homology among dopamine D2-like receptors, discovering ligands capable of discriminating between the D2, D3, and D4 receptor subtypes remains a significant challenge. Previous work has exemplified the use of bitopic ligands as a powerful strategy in achieving subtype selectivity for agonists and antagonists alike. Inspired by the potential for chemical modification of the D3 preferential agonists (+)-PD128,907 (1) and PF592,379 (2), we synthesized bitopic structures to further improve their D3R selectivity. We found that the (2S,5S) conformation of scaffold 2 resulted in a privileged architecture with increased affinity and selectivity for the D3R. In addition, a cyclopropyl moiety incorporated into the linker and full resolution of the chiral centers resulted in lead compound 53 and eutomer 53a that demonstrate significantly higher D3R binding selectivities than the reference compounds. Moreover, the favorable metabolic stability in rat liver microsomes supports future studies in in vivo models of dopamine system dysregulation.
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U2 - 10.1021/acs.jmedchem.9b00702
DO - 10.1021/acs.jmedchem.9b00702
M3 - Article
C2 - 31257877
AN - SCOPUS:85069620922
SN - 0022-2623
VL - 62
SP - 6287
EP - 6314
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 13
ER -