ABSTRACT
Aim: The σ1 receptor is a druggable target involved in many physiological processes and diseases. To clarify its physiology and derive therapeutic benefit, nine analogs based on the σ1 antagonist PB212 were synthesized replacing the 4-methylpiperidine with basic moieties of varying size and degree of conformational freedom. Results & methodology: 3-Phenylpyrrolidine, 4-phenylpiperidine or granatane derivatives displayed the highest affinity (Ki.#x00A0;= 0.12, 0.31 or 1.03 nM). Calcium flux assays in MCF7σ1 cells indicated that the highest σ1 receptor affinity are σ1 antagonists. Molecular models provided a structural basis for understanding the σ1 affinity and functional activity of the analogs and incorporated Glennon's σ1 pharmacophore model. Conclusion: Herein, we identify new compounds exploitable as therapeutic drug leads or as tools to study σ1 receptor physiology.
Subject(s)
Naphthalenes/chemistry , Naphthalenes/pharmacology , Piperidines/chemistry , Piperidines/pharmacology , Receptors, sigma/antagonists & inhibitors , Receptors, sigma/chemistry , Humans , Models, Molecular , Molecular Structure , Naphthalenes/chemical synthesis , Optical Imaging , Piperidines/chemical synthesis , Receptors, sigma/metabolism , Tumor Cells, Cultured , Sigma-1 ReceptorABSTRACT
Despite the promising potentials of σ2 receptors in cancer therapy and diagnosis, there are still ambiguities related to the nature and physiological role of the σ2 protein. With the aim of providing potent and reliable tools to be used in σ2 receptor research, we developed a novel series of fluorescent σ2 ligands on the basis of our previous work, where high-affinity σ2 ligand 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]piperazine (1, PB28) was used as the pharmacophore. Compared to the previous compounds, these novel ligands displayed improved fluorescence and σ2 binding properties, were σ2-specifically taken up by breast tumor cells, and were successfully employed in confocal microscopy. Compound 14, which was the best compromise between pharmacological and fluorescent properties, was successfully employed in flow cytometry, demonstrating its potential to be used as a tool in nonradioactive binding assays for studying the affinity of putative σ2 receptor ligands.
Subject(s)
Piperazines/chemical synthesis , Receptors, sigma/metabolism , Animals , Flow Cytometry , Fluorescence , Guinea Pigs , Humans , Ligands , MCF-7 Cells , Male , Piperazines/metabolism , RatsABSTRACT
σ2 Receptors are promising biomarkers for cancer diagnosis given the relationship between the proliferative status of tumors and their density. With the aim of contributing to the research of σ2 receptor Positron Emission Tomography (PET) probes, we developed 2-[3-[6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl]propyl]-3,4-dihydroisoquinolin-1(2H)-one (3), with optimal σ2 pharmacological properties and appropriate lipophilicity. Hence, 3 served as the lead compound for the development of a series of dihydroisoquinolinones amenable to radiolabeling. Radiosynthesis for compound 26, which displayed the most appropriate σ2 profile, was developed and σ2 specific binding for the corresponding [(18)F]-26 was confirmed by in vitro autoradiography on rat brain slices. Despite the excellent in vitro properties, [(18)F]-26 could not successfully image σ2 receptors in the rat brain in vivo, maybe because of its interaction with P-gp. Nevertheless, [(18)F]-26 may still be worthy of further investigation for the imaging of σ2 receptors in peripheral tumors devoid of P-gp overexpression.
Subject(s)
Isoquinolines , Molecular Imaging , Positron-Emission Tomography , Radiopharmaceuticals , Receptors, sigma/metabolism , Animals , Brain/diagnostic imaging , Brain/metabolism , Fluorine Radioisotopes/chemistry , Fluorine Radioisotopes/metabolism , Guinea Pigs , Humans , Isoquinolines/chemical synthesis , Isoquinolines/chemistry , Male , Molecular Structure , Radiopharmaceuticals/chemistry , Radiopharmaceuticals/metabolism , Rats , Rats, Wistar , Receptors, Serotonin/metabolism , Receptors, Serotonin, 5-HT1/metabolismABSTRACT
1-Cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine 1 (PB28) and 2-Methoxy-5-methyl-N-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)butyl]benzamide 2 (RHM-1) represent leads for tumor diagnosis, given their high affinity at σ(2) receptors. With the purpose of obtaining good candidates for σ(2) PET tracers development, hybrid structures between 1 and 2 were designed. Excellent σ(1)/σ(2) selectivities were reached when 6,7-dimethoxytetrahydroisoquinoline was linked to an o-methoxy substituted arylamide (11a, 12a, 15a), and for these benzamides an intramolecular H-bond in the active conformation at the σ sites, was hypothesized. However these excellent σ(2) ligands were accompanied by interaction with P-gp, which may limit their use as σ(2) receptor PET agents when tumors overexpress P-gp. Compound 15a whose P-gp interaction was just moderate represents an interesting tool for the development of σ(2) PET tracers useful in tumors overexpressing P-gp.
