Design and synthesis of dual 5-HT1A and 5-HT7 receptor ligands

Abstract

5-HT1A and 5-HT7 receptors have been at the center of discussions recently due in part to their major role in the etiology of major central nervous system diseases such as depression, sleep disorders, and schizophrenia. As part of our search to identify dual targeting ligands for these receptors, we have carried out a systematic modification of a selective 5HT7 receptor ligand culminating in the identification of several dual 5-HT1A and 5-HT7 receptor ligands. Compound 16, a butyrophenone derivative of tetrahydroisoquinoline (THIQ), was identified as the most potent agent with low nanomolar binding affinities to both receptors. Interestingly, compound 16 also displayed moderate affinity to other clinically relevant dopamine receptors. Thus, it is anticipated that compound 16 may serve as a lead for further exploitation in our quest to identify new ligands with the potential to treat diseases of CNS origin.

Recognition of repulsive and attractive regions of selected serotonin receptor binding site using FMO-EDA approach

“…Ligand 1 was bound into all receptors with comparable potency (PIE was − 180.0, − 169 and − 188 kcal/mol, respectively), although experimental studies showed strong activity at 5-HT 1A receptor and moderate with respect to the remaining ones. Since 1 acts as a 5-HT 1A and 5-HT 2A agonist, and 5HT 7 receptor antagonist (such as aripiprazole [45,58]), Fig. 4 analysis allowed to hypothesize about its molecular mechanism of activation/deactivation of receptors.…”

Synthesis and evaluation of the structural elements in alkylated tetrahydroisoquinolines for binding to CNS receptors

“…19 Inspired by the promising binding affinity profiles of these butyrophenones at the relevant CNS receptors ( Table 3 ), we embarked on an exploration to further understand the SAFIR of these compounds. To begin with, we sought to understand the role of the position of the nitrogen in segment C. The THIQ moiety in 3b was replaced with tetrahydroquinoline and 2,3,4,5-tetrahydro-1H-benzo[ b ]azepine to produce compounds 3c and 3d respectively, resulting in the formation of aromatic nitrogen atoms in both analogs.…”

“… MTA = Missed 50% of threshold inhibition, ND = Not determined. * Ki values without the associated SEM, are within 20% of the mean value. ** Binding affinity data from reference 19. a Binding affinity data from reference 28. b Binding affinity data from reference 29; c Binding affinity data from reference 30 …”

“…15-17 We have previously reported that the tetrahydroisoquinoline (THIQ) moiety, appropriately substituted with arylalkyl groups such as benzothiazole alkyl groups or halobutyrophenones could produce agents that provide differential binding profiles at clinically relevant CNS receptors including serotonin (5-HT) and dopamine (DA) receptor subtypes. 18, 19 In this manuscript, we further explore changes in three segments (A, B and C) of compound 1a (Figure 1 ) in order to understand the structure-affinity relationships (SAFIRs) associated with this lead molecule.…”

New analogs of SYA013 as sigma-2 ligands with anticancer activity

“…Compound 3 was previously synthesized and reported by us [14]. The synthetic methods leading to alkylating agents 14, 15, 16 and 17 were also previously reported [14], [15], [16]. Compounds 4 -8 were synthesized as described in Scheme 1a.…”