Photochromic Dopamine Receptor Ligands Based on Dithienylethenes and Fulgides.

We describe the incorporation of the well-investigated class of photochromic dithienylethenes (DTEs) and fulgides into known dopamine receptor ligands such as 1,4-disubstituted aromatic and hydroxybenzoxazinone piperazines as well as aminoindanes. Subtype and functional selective photochromic ligands were obtained and characterized by NMR and UV/VIS spectroscopic measurements. The photophysical properties of the DTE based dopamine ligands revealed a high fatigue resistance for the diarylmaleimides, but the ringclosure could not be accomplished in polar solvents due to a known twisted intramolecular charge transfer (TICT). Several cyclopentene-DTEs showed high PSS, but a fast degradation by forming an irreversible byproduct. Focusing on the fulgides, high photostationary states and switching in polar solvents were possible. The compounds 43, 45 and 46 containing the isopropyl group showed only isomerization between the open E-form and the closed C-form. At a concentration of 1 nm, the cyclopentene-DTE 29-open showed a more than 11-fold higher activation of D2S , a pharmacologically important G protein-coupled receptor, than its photochromic congener 29-closed. Interestingly, the fulgimide-based pair 52-(E)-open/52-closed could be discovered as an alternative photoswitch with inverse activation properties exhibiting four-fold higher activity in the closed state.

ß-Arrestin biased dopamine D2 receptor partial agonists: Synthesis and pharmacological evaluation.

ß-Arrestin biased G protein-coupled receptor ligands represent important molecular probes and may increase favorable drug action and safety as novel therapeutics. Starting from recently discovered hydroxy-substituted heterocyclic piperazine scaffolds, we have developed a series of dopamine D2 receptor ligands with a pyrazolo[1,5-a]pyridine as secondary pharmacophore that is functionalized in position 3 by a formyl or hydroxyiminomethyl substituent. The ligands, especially the benzoxazinone 9d, were found to stimulate substantial ß-arrestin-2 recruitment, while being nearly devoid of activity in a GTPγS binding assay. Investigating a new series of truncated analogs lacking a secondary pharmacophore, considerable ß-arrestin-2 recruitment in the absence of G protein activation was found, when a 5-hydroxy-2H-benzo[b][1,4]oxazin-3(4H)-one was combined with an N-propyl-substituted 1,4-diazepane (15c). Although 15c displayed reduced potency compared to 9d, the dose-response curves indicate that a hydroxy-substituted heterocyclic primary pharmacophore is sufficient for the functionally selective activation of D2R.

Hydroxy-Substituted Heteroarylpiperazines: Novel Scaffolds for ß-Arrestin-Biased D2R Agonists.

By means of a formal structural hybridization of the antipsychotic drug aripiprazole and the heterocyclic catecholamine surrogates present in the ß2-adrenoceptor agonists procaterol and BI-167107 (4), we designed and synthesized a collection of novel hydroxy-substituted heteroarylpiperazines and heteroarylhomopiperazines with high dopamine D2 receptor (D2R) affinity. In contrast to the weak agonistic behavior of aripiprazole, these ligands are capable of effectively mimicking those interactions of dopamine and the D2R that are crucial for an active state, leading to the recruitment of ß-arrestin-2. Interestingly, some ligands show considerably lower intrinsic activity in guanine nucleotide exchange experiments at D2R and consequently represent biased agonists favoring ß-arrestin-2 recruitment over canonical G protein activation. The ligands' agonistic properties are substantially driven by the presence of an endocyclic H-bond donor.

Structure-Guided Screening for Functionally Selective D2 Dopamine Receptor Ligands from a Virtual Chemical Library.

Functionally selective ligands stabilize conformations of G protein-coupled receptors (GPCRs) that induce a preference for signaling via a subset of the intracellular pathways activated by the endogenous agonists. The possibility to fine-tune the functional activity of a receptor provides opportunities to develop drugs that selectively signal via pathways associated with a therapeutic effect and avoid those causing side effects. Animal studies have indicated that ligands displaying functional selectivity at the D2 dopamine receptor (D2R) could be safer and more efficacious drugs against neuropsychiatric diseases. In this work, computational design of functionally selective D2R ligands was explored using structure-based virtual screening. Molecular docking of known functionally selective ligands to a D2R homology model indicated that such compounds were anchored by interactions with the orthosteric site and extended into a common secondary pocket. A tailored virtual library with close to 13 000 compounds bearing 2,3-dichlorophenylpiperazine, a privileged orthosteric scaffold, connected to diverse chemical moieties via a linker was docked to the D2R model. Eighteen top-ranked compounds that occupied both the orthosteric and allosteric site were synthesized, leading to the discovery of 16 partial agonists. A majority of the ligands had comparable maximum effects in the G protein and ß-arrestin recruitment assays, but a subset displayed preference for a single pathway. In particular, compound 4 stimulated ß-arrestin recruitment (EC50 = 320 nM, Emax = 16%) but had no detectable G protein signaling. The use of structure-based screening and virtual libraries to discover GPCR ligands with tailored functional properties will be discussed.