N-Skatyltryptamines—Dual 5-HT6R/D2R Ligands with Antipsychotic and Procognitive Potential

Abstract

A series of N-skatyltryptamines was synthesized and their affinities for serotonin and dopamine receptors were determined. Compounds exhibited activity toward 5-HT1A, 5-HT2A, 5-HT6, and D2 receptors. Substitution patterns resulting in affinity/activity switches were identified and studied using homology modeling. Chosen hits were screened to determine their metabolism, permeability, hepatotoxicity, and CYP inhibition. Several D2 receptor antagonists with additional 5-HT6R antagonist and agonist properties were identified. The former combination resembled known antipsychotic agents, while the latter was particularly interesting due to the fact that it has not been studied before. Selective 5-HT6R antagonists have been shown previously to produce procognitive and promnesic effects in several rodent models. Administration of 5-HT6R agonists was more ambiguous—in naive animals, it did not alter memory or produce slight amnesic effects, while in rodent models of memory impairment, they ameliorated the condition just like antagonists. Using the identified hit compounds 15 and 18, we tried to sort out the difference between ligands exhibiting the D2R antagonist function combined with 5-HT6R agonism, and mixed D2/5-HT6R antagonists in murine models of psychosis.

Multitarget Derivatives of D2AAK1 as Potential Antipsychotics: The Effect of Substitution in the Indole Moiety

“…This may lead to the malfunction of interneurons as manifested by cognitive, social dysfunction and behavioral disturbances through altered effects on a wide range of micro‐ and macro‐ systems [13,14] . More recent studies on the treatment of schizophrenia focus on the search for multitarget compounds with increased affinity for serotonin receptors and decreased or preserved affinity for the dopamine receptor [15–17] …”

“…[13,14] More recent studies on the treatment of schizophrenia focus on the search for multitarget compounds with increased affinity for serotonin receptors and decreased or preserved affinity for the dopamine receptor. [15][16][17] In our previous studies we performed structure-based virtual screening [18] and identified, among others, virtual hit D2AAK1 [19] (see Figure 1) which displays nanomolar affinity to dopamine D 2 and D 3 as well as serotonin 5-HT 1A and 5-HT 2A receptors. Here we present the next step in our optimization campaign of D2AAK1 [20,21] From previously reported D2AAK1 derivatives, [21] we chose the most promising 3-(1-benzyl-1,2,3,6tetrahydropyridin-4-yl)-5-ethoxy-1H-indol (Figure 1).…”

New Triazine Derivatives as Serotonin 5-HT6 Receptor Ligands

“…Furthermore, the modifications introduced to the lead MST4 led also to promising multi-target structures acting on several targets simultaneously, e.g., three targets (5-HT 6 R, 5-HT 2A R and D 2 R, such as in compound 25 (K i = 78 nM vs. K i = 364 nM vs. K i = 149 nM, respectively)). Compounds acting on two such targets, i.e., 5-HT 6 R and D 2 R [ 31 ] or 5-HT 6 R and 5-HT 2A R [ 32 ], are described in the literature, but such three-target ligands are not yet available.…”

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

“…In addition to the above-mentioned 1,4-DACA, some specific fragments were used as primary pharmacophores, namely 7piperazinyl and 7-piperidinyl-3,4-dihydroquinazolin-2(1H)-one, 778 5-piperidinyl and 5-piperazinyl-1H-benzo[d]midazole-2(3H)-one, 779 4-(1-benzimidazolinone)piperidine, 780 sumanirole, 489,490,776,777 tranylcypromine, 472 pramipexole, 469 2phenylcyclopropylmethylamine, 527 eticlopride, 479,775 1,2,3,4-tetrahydro-3-quinolinamine, 776 tetracyclic, 781 tetrahydroisoquinoline, 480,498,594,595,600,[782][783][784][785][786][787] or 1,3-disubstituted morpholine. 438,474,490,493,788 Various aliphatic, 477,515,516,602,[789][790][791][792][793] bicyclic [794][795][796][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,…”