Conformationally-flexible benzamide analogues as dopamine D3 and σ2 receptor ligands

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

“…However, 97 binds with 10-fold greater affinity at σ 1 receptors than at σ 2 receptors whereas 98 binds equally well at both population; on the basis of these and related studies they suggested that phenylpropyl derivatives, rather than phenylethyl derivatives, might provide leads to agents with greater σ 2 selectivity. More recently, Mach et al (2004) have reported on a very interesting series of tetrahydroisoquinolines. Compound 99 (Ki = 8.2 nM), for example, binds with high affinity, and displays 1,573-fold selectivity versus σ 1 binding; interestingly, the related but shorter analog 100 (Ki = 89.4 nM) binds with lower affinity and is several-fold selective for σ 1 receptors.…”

“…Berardi et al, 1998;Berardi et al, 2004;Fujimura et al, 1997;Kawamura et al, 2003;Mach et al, 2004;Maeda et al, 2002;Maier and Wunsch, 2002;Marrazzo et al, 2001;Matsumoto et al, 2004). Of particular interest is a series of substituted tetralins bearing a gem-dimethyl piperidine.…”

Synthesis, Functionalization, and Design of Magnetic Nanoparticles for Theranostic Applications

“…[575] Other examples of small molecule as targeting ligands are selectin, [576] selegiline, [577] curcumin, [578] triphenylphosphonium (TPP), [579] and benzamides (anisamide, in particular). [580] But more importantly, carbohydrates have gained more interests for their low molecular weight, inexpensive manufacturing, and efficient modification and characterization by well-known sugar chemistries to serve as nanoparticle small molecule targeting ligands. Lectin receptors, especially asialoglycoprotein receptors (ASGPR), [581] which are expressed on the cellular membrane of a number of cells have been the main targets of nanoparticles decorated with carbohydrate moieties such as galactose, [582] mannose, [583] and glucose.…”

Imaging the Sigma-2 Receptor for Diagnosis and Prediction of Therapeutic Response

“…These compounds were identified in an SAR study of the benzamide analog, YUN250, that was developed as a dopamine D 3 -selective ligand ( Figure 3A) [35]. The relatively high lipophilicity of YUN250 (log P = 5.76) suggests that it is not capable of readily crossing the blood-brain barrier and being active in behavioral studies.…”

“…In order to reduce the lipophilicity of YUN250, the 4-(2,3-dichlorophenyl) piperazine moiety of YUN250 was replaced with other aromatic amine groups. Although this strategy resulted in a number of useful dopamine D 3 receptor ligands [36], it was also observed that replacement of the 4-phenylpiperazine moiety with a 6,7-dimethoxy-1,2,3,4-tetrahydroisoqinoline ring resulted in compounds having a high affinity and excellent selectivity for σ 2 versus σ 1 receptors, and a dramatic reduction in affinity for dopamine receptors [35]. As discussed in greater detail below, the conformationally-flexible benzamide analogs have proven to be an important class of σ 2 -selective compounds for the preparation of radiolabeled probes to image this receptor in vitro and in vivo.…”