Chiral Cyclic Aliphatic Linkers as Building Blocks for Selective Dopamine D₂ or D₃ Receptor Agonists

Abstract

Linkers are emerging as a key component in regulating the pharmacology of bitopic ligands directed toward G-protein coupled receptors (GPCRs). In this study, the role of regio- and stereochemistry in cyclic aliphatic linkers tethering well-characterized primary and secondary pharmacophores targeting dopamine D2 and D3 receptor subtypes (D2R and D3R, respectively) is described. We introduce several potent and selective D2R ( rel-trans-16b; D2R K i = 4.58 nM) and D3R ( rel-cis-14a; D3R K i = 5.72 nM) agonists while modulating subtype selectivity in a stereospecific fashion, transferring D2R selectivity toward D3R via inversion of the stereochemistry around these cyclic aliphatic linkers [e.g., (−)-(1S,2R)-43 and (+)-(1R,2S)-42]. Pharmacological observations were supported with extensive molecular docking studies. Thus, not only is it an innovative approach to modulate the pharmacology of dopaminergic ligands described, but a new class of optically active cyclic linkers are also introduced, which can be used to expand the bitopic drug design approach toward other GPCRs.

Recent advances in dopamine D2 receptor ligands in the treatment of neuropsychiatric disorders

“…In the following parts, we designated the D 2 R modulators that do not structurally fit into the 1,4‐DACA group or did not contain the necessary data (top‐ranked candidate evaluated in vivo as a potential drug for management of schizophrenia, PD, depression or anxiety, or proved to be selective D 2 R, biased or bivalent ligand) so we discussed them in detail in section “2.5 1,4‐Disubstituted aromatic/heteroaromatic cyclic amine derivatives affecting dopamine D 2 Rs—their structure, function, and pharmacological profiles.” These analogs fall within the more general pharmacophore of D 2 R and even D 3 R, as shown in Figure 64. This pharmacophore consists of the so‐called primary pharmacophore, which is further composed of aromatic/heteroaromatic head and amine moieties, a central linker, and a so‐called secondary pharmacophore 490,527,775–777 . The primary pharmacophore binds to the orthosteric binding site, whereas the secondary pharmacophore binds to the allosteric (secondary) binding site 776,777 .…”

“…Various aliphatic, 477,515,516,602,789–793 bicyclic 794–797 or spirocyclic 798 amines have also been used for amine moiety. Generally, ligands with D 2 R selectivity were obtained using sumanirole 489,490,776,777 ( 1 , Figure 7) or 2‐phenylcyclopropylmethylamine 527 as a primary pharmacophore. On the other hand, eticlopride‐ 775 or tetrahydroisoquinoline‐based 480,498,782,785 derivatives exhibited D 3 R selectivity.…”

“…The aliphatic ether was further modified by adding a double bond, 788 a triple bond, an aromatic, cyclohexyl ring or a cyclopropyl rings, 584,800 or switched to a cyclic ether, 483,793,801 thio‐ether, 488,670,672 an aliphatic linker without any heteroatom 599,600,670,672,802 or an aromatic amine 478 . Furthermore, aliphatic secondary amide was modified by adding a double bond, 698 a hydroxy group, 473,479,483,490 a fluorine atom, 483 a cyclopropyl ring, 480,490,498,776,788 a cyclobutyl ring, 469,472 a cyclopentyl ring, 490 a cyclohexyl ring, 469,490 a 1,2,3‐triazole moiety, 490 or by conversion to a cyclic amide, 476,646,709 a tertiary amide, 614 an aliphatic amine, 492 an aliphatic ketone, 488,670,672,707,781 a cyclic ketone, 670 an aliphatic sulfonamide, 613,658 a cyclic sulfonamide, 708,709 a cyclic imide, 163,482,699,708,709 a 1,3,4‐oxadiazole ring 615 or a various triazole ring: 1,2,3‐triazole 597,598,603,803 or 1,2,4‐triazole 474,794–798 . In general, the incorporation of a hydroxy group in the central linker region increases the selectivity for D 3 R 469,473,479,483 .…”

“…An extensive chemical/stereochemical SAR study investigated and highlighted the importance of chirality and composition in the linkers for bitopic ligands based on 1 (Figure 7). 490 It was found that a relative trans stereochemistry in the central linker between sumanirole moiety and indole core (representative derivative 2 , moderate selective D 2 R agonist, Figure 7) retains high binding mode at D 2 R while providing selectivity for D 2 R. Furthermore, it was shown for the first time how inversion in the cycloprop‐1,2‐diyl linker stereochemistry could modulate D 2 ( 3a , moderately selective D 2 R agonist, Figure 7) or D 3 ( 3b , preferential D 3 R agonist, Figure 7) receptor preferential binding in a diastereospecific way, independently from the lipophilic appendage (Figure 12). In the computational studies, the authors identified an area of nonconservation amino acid sequence in the EL2 region of D 2 and D 3 receptors, which may dictate the subtype selectivity 490 …”

Approach to the specificity and selectivity between D2 and D3 receptors by mutagenesis and binding experiments part I: Expression and characterization of D2 and D3 receptor mutants

“…The structure of D3R antagonist bound was crystallized in 2010, 70 further nourishing the approaches of molecular modeling aiming to the same goal: finding ligands that are D3 preferred over D2. 62,[71][72][73][74] Furthermore, the selectivity issue is also to be discussed as it becomes obvious that many compounds are not binding only to dopamine receptors, but also to other GPCR family(es). 75 Although directed mutagenesis is a key player in the understanding of the structure-activity of receptors, together with co-crystallography of pure receptor-ligand complexes, the number of such mutants for D2 or D3 is rather scarce in the literature (see Table 5 for a summary).…”