The Significance of Chirality in Drug Design and Synthesis of Bitopic Ligands as D₃ Receptor (D₃R) Selective Agonists

Abstract

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.

Exception That Proves the Rule: Investigation of Privileged Stereochemistry in Designing Dopamine D3R Bitopic Agonists

“…We demonstrated how canonical D 3 R preferential agonists, such as pramipexole, PF592379 (1), and (+)-PD128907 ((+)-(4aR,10bR)-2)), exhibit low selectivity in optimized binding assays using the agonist radioligand [ 3 H]-(R)-(+)-7-OH-DPAT. 29 Alternatively, through our bitopic drug design strategy, we have been able to generate the most selective D 3 R full agonist reported to date, FOB02-04A (5) (Figure 1). 29 A similar drug design has resulted in some of the most selective and potent D 2 R G-protein biased agonists reported.…”

“…30,31 Starting from 5, we further investigated the chemical space around the linker, via insertion of a hydroxyl substituent and ring-expansion into a trans-cyclohexyl scaffold (Figure 1). Inspired by previous observations, 29 we explored the chiral requirements of (+)-(4aR,10bR)-2 (nonselective D 3 R agonist) by synthesizing bitopic analogues in all the cis and trans combinations of its 9-methoxy-3,4,4a,10b-tetrahydro-2H,5Hchromeno [4,3-b] [1,4]oxazine scaffold (Figure 1).…”

“…We previously demonstrated that 1 is a suitable PP to be used in bitopic molecule design. 29 We showed that to generate high affinity and selective bitopic ligands an inversion of configuration at its (2R) stereocenter was necessary. Indeed, when in a bitopic configuration with a N-butyl-1H-indole-2-carboxamide SP (3 and 4), the (2S,5S) conformation of the PP in 4 resulted in a privileged architecture with >1000-fold increased affinity, and consequent selectivity for the D 3 R with respect to its (2R,5S) eutomer.…”

“…29 Full resolution of the chiral centers in the linker enabled further analysis of stereochemistry on affinity and selectivity of the bitopic molecules 5 and 6, identifying 5 as the current lead (Figure 1). 29 Inspired by our previous work on D 3 R antagonists, we expanded the linker chemical space, utilizing molecular fragments known to induce D 3 R recognition selectively. Both compounds SB269952 (7) and SB277011A (8) (Figure 1) present a trans-cyclohexyl moiety in the linker, both demonstrate selective D 3 R binding, and interstingly 7 shows a unique noncompetitive antagonist profile at D 2 R. 32−34 Similarly, a hydroxyl substituent in the butyl linking chain provided the most D 3 R selective antagonists hitherto reported, 9, 8 currently under investigation for treatment of opioid use disorders.…”

Design and Synthesis of Bitopic 2-Phenylcyclopropylmethylamine (PCPMA) Derivatives as Selective Dopamine D3 Receptor Ligands

“…The significance of chirality is a critical consideration in medicinal chemistry and has also been showcased in previous D3R ligand discovery. 17 With respect to the chiral centers on the PCPMA skeleton, although all compounds were synthesized as the trans isomers, they were tested as a mixture of (1R,2R) and (1S,2S) isomers in our primary screening. We thus selected the four best compounds, 22e, 30p, 30q, and 30r, for chiral separations and further pharmacological profiling.…”