Methods for addressing sigma receptor affinity and activity have been explored and although several protocols have been employed, only few procedures resulted reliable. Sigma-1 receptor affinity ...protocol using guinea-pig brain and (+)-(3)H-pentazocine and sigma-2 receptor affinity protocol employing rat liver and (3)H-DTG are usually reported by authors as standard procedures. By contrast, the intrinsic activity evaluation of sigma ligands has been performed in several manners: tumor cell lines, isolated organ bath, in vivo animal model. The last is not considered in the present paper because this method studied the physiological role of sigma receptors. The studies carried out in tumor cell lines involved the role of sigma receptors in tumors progression while, although isolated organ bath experiment employed physiological samples, the pharmacokinetic properties of ligands, a strictly requirement for the in vivo assays, did not affect the pharmacodynamic properties of tested compounds. The advances in the above mentioned assays have been reported.
Herein the evolution in the development of new sigma (sigma) receptor ligands since the middle '90s by our research group is reported. In the effort to contribute to the identification of the ...structural features for high-affinity ligands selective 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 sigma 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 sigma(2) receptor ligands were found among N-cyclohexylpiperazine derivatives, such as 1-cyclohexyl-4-3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propylpiperazine (3) (PB 28), when they were assayed in radioligand binding with (3)H-DTG in rat liver. Unfortunately, these ligands were all devoid of a significant selectivity relative to sigma(1) receptor whose binding was assayed with (+)-(3)H-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 sigma(2) versus sigma(1) receptor binding selectivity in MCF7 and MCF7 ADR tumor cell lines respectively. In the class of piperazines, also high-affinity sigma(1) receptor ligands were found, possibly due to the presence of a double N-atom and an additional reverse mode of binding. Piperidine derivatives were investigated as high-affinity and selective sigma(1) receptor ligands leading to some 3,3-dimethylpiperidines such as 3,3-dimethyl-1-3-(6-methoxynaphthalen-1-yl)propylpiperidine (69) which resulted to be highly selective relative to the sigma(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 sigma(1) relative to sigma(2) receptor ligand.
P-glycoprotein (P-gp, MDR1) is a membrane transporter expressed in several regions of our body. It plays a crucial defense role as it mediates the efflux of hundreds of potentially toxic substances. ...However, P-gp is one of the main causes of failure in cancer chemotherapy, as a number of chemotherapeutic agents are P-gp substrates. Another interesting implication concerns the correlation between P-gp expression impairment and the onset of several central nervous system pathologies such as Alzheimer's and Parkinson's diseases. In view of these considerations, in the present study, a new series of P-gp modulators have been designed, synthesized and evaluated for their activity towards P-gp and two other sister proteins (BCRP and MRP1). The compounds, structurally correlated to the potent but non-selective P-gp inhibitor
MC70
4′-(6,7-dimethoxy-3,4-dihydro-1
H
-isoquinolin-2-ylmethyl)biphenyl-4-ol, proved fairly selective towards P-gp, with a potency in the micromolar range. Compounds
5a
,
5d
and
12d
proved capable of restoring doxorubicin toxicity in resistant cancer cells.
Among the new selective P-gp modulators reported, compound
12a
almost completely restores doxorubicin cytotoxicity in resistant cancer cells.
Among the new selective P-gp modulators reported, compound
12a
almost completely restores doxorubicin cytotoxicity in resistant cancer cells.
P-glycoprotein (P-gp, MDR1) is a membrane transporter ...expressed in several regions of our body. It plays a crucial defense role as it mediates the efflux of hundreds of potentially toxic substances. However, P-gp is one of the main causes of failure in cancer chemotherapy, as a number of chemotherapeutic agents are P-gp substrates. Another interesting implication concerns the correlation between P-gp expression impairment and the onset of several central nervous system pathologies such as Alzheimer's and Parkinson's diseases. In view of these considerations, in the present study, a new series of P-gp modulators have been designed, synthesized and evaluated for their activity towards P-gp and two other sister proteins (BCRP and MRP1). The compounds, structurally correlated to the potent but non-selective P-gp inhibitor
MC70
4′-(6,7-dimethoxy-3,4-dihydro-1
H
-isoquinolin-2-ylmethyl)biphenyl-4-ol, proved fairly selective towards P-gp, with a potency in the micromolar range. Compounds
5a
,
5d
and
12d
proved capable of restoring doxorubicin toxicity in resistant cancer cells.
The title compound, C
24
H
25
NO
3
·2CH
3
OH, which crystallized as a methanol disolvate, has applications as a PET radiotracer in the early diagnosis of Alzheimer's disease. The dihedral angle ...between the biphenyl rings is 8.2 (2)° and the heterocyclic ring adopts a half-chair conformation with the N atom adopting a pyramidal geometry (bond-angle sum = 327.6°). The C atoms of both methoxy groups lie close to the plane of their attached ring deviations = 0.107 (6) and 0.031 (6) Å. In the crystal, the components are linked by O—H...O and O—H...N hydrogen bonds, generating 010 chains. C—H...O interactions are also observed.
The title compound, C
24
H
25
NO
3
·2CH
3
OH, which crystallized as a methanol disolvate, has applications as a PET radiotracer in the early diagnosis of Alzheimer’s disease. The dihedral angle ...between the biphenyl rings is 8.2 (2)° and the heterocyclic ring adopts a half-chair conformation with the N atom adopting a pyramidal geometry (bond-angle sum = 327.6°). The C atoms of both methoxy groups lie close to the plane of their attached ring deviations = 0.107 (6) and 0.031 (6) Å. In the crystal, the components are linked by O—H⋯O and O—H⋯N hydrogen bonds, generating 010 chains. C—H⋯O interactions are also observed.
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