<![CDATA[Binding characteristics of sigma2 receptor ligands]]>

Deconstruction of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline moiety to separate P-glycoprotein (P-gp) activity from σ2 receptor affinity in mixed P-gp/σ2 receptor agents

“…However, these data were in contrast with results from conformationally constrained σ 2 receptor ligands (e.g. 1-cyclohexyl-4-(4-arylcyclohexyl)piperazines, and steroids) and with previous comparative molecular field analysis, whose high-affinity binding suggests that the interaction of the ligands in the folded conformation is unlikely [22,36,37]. …”

Classes of Sigma2 (&#x3C3;2) Receptor Ligands: Structure Affinity Relationship (SAfiR) Studies and Antiproliferative Activity

“…Their affinities were much lower than the agonists cyclohexylpiperazine used to generate the above described model [52]. According to this model a 2 interaction site is formed by two hydrophobic regions and a H-donor area in the middle, similarly to the model obtained by CoMFA and in line with the 2 binding characteristics proposed for 2 receptor ligands [53].…”

Synthesis and evaluation of tetrahydroindazole derivatives as sigma-2 receptor ligands

“…Though the exact binding requirement of the sigma-2 receptor still remains unclear, a number of publications have reported that sigma-2 receptor binding profile consists of one basic nitrogen (BN) for electrostatic interaction or hydrogen bonding, one primary hydrophobic binding (PHB) site, one secondary hydrophobic binding (SHB) site, and an additional hydrophobic binding (AHB) site. 4,[38][39][40][41][42][43][44][45][46] According to the binding profile, the 4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide structure of analog 12 fits into the PHB site with the 9-aza nitrogen as the BN and the bicyclo[3.3.1]nonane structure fitting into the AHB site ( Figure 1). There is no hydrophobic moiety for the SHB.…”

“…There are several binding models proposed in the literature for sigma-2 receptor ligands. [38][39][40][41][42][43][44][45][46] Each of them was based on a limited set of sigma-2 ligands and thus can only explain the structurally similar analogs and have no predictive value on other structurally unrelated sigma-2 receptor ligands. Common elements of the various binging models of the sigma-2 receptor binding region include one hydrogen bond or electrostatic interaction site and at least two hydrophobic pockets.…”