Classes of sigma2 ( o-2) receptor ligands: structure affinity relationship (SAfiR) studies and antiproliferative activity

Although several pieces of information are still missing about sigma-2 receptor, the production of high affinity sigma-2 receptor ligands allowed important acquisitions. Morphans such as CB64D and CB184 were the first truly 2-selective ligands synthesized, and their use in cell cultures highlighted the relationship between sigma-2 receptors and cell proliferation, shedding light on important diagnostic and therapeutic potentials with which sigma-2 ligands are endowed. The most significant classes of compounds are herein discussed. The design and Structure-Affinity Relationship studies (SAfiR) of 2 receptor ligands belonging to the classes of morphans, indoles (siramesine analogues), granatanes, flexible benzamides and N-cyclohexylpiperazines are reported, together with the biological results which these compounds provided giving a crucial contribution to the sigma-2 receptor research. The pharmacophore models which were generated on the basis of different classes of the sigma-2 ligands and the attempts for 2 receptor purification are briefly described

Live imaging reveals a new role for the sigma-1 (σ1) receptor in allowing microglia to leave brain injuries

Microglial cells are responsible for clearing and maintaining the central nervous system (CNS) microenvironment. Upon brain damage, they move toward injuries to clear the area by engulfing dying neurons. However, in the context of many neurological disorders chronic microglial responses are responsible for neurodegeneration. Therefore, it is important to understand how these cells can be “switched-off” and regain their ramified state. Current research suggests that microglial inflammatory responses can be inhibited by sigma () receptor activation. Here, we take advantage of the optical transparency of the zebrafish embryo to study the role of 1 receptor in microglia in an intact living brain. By combining chemical approaches with real time imaging we found that treatment with PB190, a 1 agonist, blocks microglial migration toward injuries leaving cellular baseline motility and the engulfment of apoptotic neurons unaffected. Most importantly, by taking a reverse genetic approach, we discovered that the role of 1 in vivo is to “switch-off” microglia after they responded to an injury allowing for these cells to leave the site of damage. This indicates that pharmacological manipulation of 1 receptor modulates microglial responses providing new approaches to reduce the devastating impact that microglia have in neurodegenerative diseases

Rigid versus flexible anilines or anilides confirm the bicyclic ring as the hydrophobic portion for optimal σ2 receptor binding and provide novel tools for the development of future σ2 receptor PET radiotracer

Despite their uncertain identification, s2 receptors are promising targets for the development of diagnostics and therapeutics for tumor diseases. Among the s2 ligands developed, the class of the flexible benzamides furnished an optimal pharmacophore for s2 receptor high affinity ligands. A recent investigation suggested that flexible benzamides bind s2 receptors in a bicyclic-like conformation due to an intramolecular H-bond, with 3,4-dihydroisoquinolinone derivatives reaching excellent s2 affinity and selectivity. Herein, the bicyclic-preferred conformation for s2 binding was confirmed through the development of 3,4- dihydroquinolin-(1H)2-one isomeric derivatives, 1,2,3,4-tetrahydroquinolines and the corresponding flexible anilides and anilines, all linked to the 6,7-dimethoxytetrahydroisoquinoline as a basic moiety. 3,4- Dihydroisoquinolin-(1H)2-one (10a) and 1,2,3,4-tetrahydroisoquinoline (11b) emerged for high s2 affinity combined to an excellent s2 versus s1 selectivity. In particular, compound 11b with its low nanomolar s2 affinity and impressive 2807-fold s2 versus s1 selectivity largely exceeded the biological profile of the best 3,4-dihydroisoquinolin-(2H)1-one reference compounds (1). Because of the absence of a cytotoxic effect, the modest interaction with the P-gp, an appropriate lipophilicity and the presence of easily radiolabeling functions, 11b deserves further investigation for the imaging of s2 receptors via PET in tumor

A Structure-Affinity and Comparative Molecular Field Analysis of Sigma-2 (σ2) Receptor Ligands

Several 1 receptor ligands with sub-nanomolar affinity and excellent selectivity have been reported, but rela-tively few 2-selective ligands are known. 1-Cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (PB28; 1) has been reported by us as a high-affinity 2 receptor ligand with significant 2 selectivity, and sev-eral analogs of (1) now have been developed. Among these are the class of cyclohexylpiperazines that display a good compromise between affinity/activity and selectivity for 2 receptors. Very little is currently known about the nature of 2receptors. In the absence of structure-based receptor information, we applied a comparative molecular field analysis (CoMFA) – a three-dimensional structure-activity relationship (3D-QSAR) method – to a set of cyclohexylpiperazine 2ligands to develop a predictive model that might provide information about the stereoelectronic nature of the receptor binding site. Two CoMFA models were generated from two different alignments: the first used an automated FlexS algo-rithm, and the second used a rationally-driven manual alignment. Significantly better predictivity was obtained with the manual alignment (TSET: q2 = 0.73, r2 = 0.95; PSET: r2 = 0.55/0.73) than from the automated alignment (TSET: q2 = 0.69, r2 = 0.98; PSET: r2 = 0.13/0.16). The resulting CoMFA maps account for observed structure-affinity relationships and suggest a possible anatomy for the 2 receptor/cyclohexylpiperazine binding sit

1-Cyclohexylpiperazine and 3,3-Dimethylpiperidine Derivatives as Sigma-1 (σ1) and Sigma-2 (σ2) Receptor Ligands: A Review

Herein the evolution in the development of new sigma () receptor ligands since the middle ’90s by our re-search group is reported. In the effort to contribute to the identification of the structural features for high-affinity ligandsselective versus serotonin, dopamine and other CNS-related receptors, two general classes of (naphthalene)alkylamine compounds were prepared and explored, with the aim of addressing the affinities toward the two recognized receptor subtypes. The common template of these compounds was mainly an unsubstituted or methoxy-substituted naphthalene or tetralin nucleus, linked by an alkyl spacer to a substituted piperazine or piperidine ring. The design of new ligands was thought keeping in mind their possible application as PET diagnostic tools and fluorescence tools. High-affinity 2 recep-tor ligands were found among N-cyclohexylpiperazine derivatives, such as 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (3) (PB 28), when they were assayed in radioligand binding with [3H]-DTG in rat liver. Unfortunately, these ligands were all devoid of a significant selectivity relative to1 receptor whose binding was assayed with (+)-[3H]-pentazocine in guinea pig brain. Nevertheless, compound 3 had previously shown to be 40-fold selective with a slightly different binding method in animals’ tissues. Moreover, it demonstrated 46-fold and 59-fold 2versus1 receptor binding selectivity in MCF7 and MCF7 ADR tumor cell lines respectively. In the class of piperazines, also high-affinity 1 receptor ligands were found, possibly due to the presence of a double N-atom and an additional re-verse mode of binding. Piperidine derivatives were investigated as high-affinity and selective 1 receptor ligands leading to some 3,3-dimethylpiperidines such as 3,3-dimethyl-1-[3-(6-methoxynaphthalen-1-yl)propyl]piperidine (69) which re-sulted to be highly selective relative to the 2 receptor. For the best ligands, functional assays were conducted in order to investigate agonist/antagonist activity. The effect of chirality in the intermediate methyl-alkyl chain was explored for a class of 4-methylpiperidines linked to some (4-chlorophenoxy)alkyl moieties, and compound (–)-(S)-92 emerged as the most selective 1 relative to 2 receptor ligand

Novel Metal Chelators Thiosemicarbazones with Activity at the sigma2 Receptors and P-glycoprotein: an Innovative Strategy for Resistant Tumors Treatment

To combat the emergence of drug-resistance in tumors novel strategies are urgently needed. With this in mind we designed a novel class of thiosemicarbazones able to target simultaneously 2 receptors and P-glycoprotein efflux pump while chelating metals such as Iron. The combined effect of these targets would lead to the activation of multiple pathways to which resistant tumors are sensitive. Indeed, most of the novel thiosemicarbazones displayed antiproliferative activity in both parent (MCF7 breast adenocarcinoma and A549 lung carcinoma) and corresponding doxorubicine-resistant cells (MCF7dx and A549dx). A few compounds emerged for their potent antiproliferative activity or for their more potent effect in doxorubicine-resistant cells than in the parent ones, while other compounds emerged for their remarkable P-gp modulatory activity. These results pave the way for further studies on these targets in the oncology field, while the availability of promising molecules for resistant tumors treatment that warrant deeper investigations was increased