Bertold J. Vilner

Ibogaine and its congeners are σ2 receptor-selective ligands with moderate affinity

Abstract Ibogaine (12-methoxyibogamine) exhibited moderate affinity for σ2 sites (Ki = 201 nM) and low affinity for σ1 sites (Ki = 8554 nM), thus showing 43-fold selectivity for σ2 receptors. Tabernanthine (13-methoxyibogamine) and (±)-ibogamine had σ2 Ki = 194 nM and 137 nM, respectively. However, they showed 3- to 5-fold higher σ1 affinity compared to ibogaine, resulting in about 14-fold selectivity for σ2 sites over σ1. A potential ibogaine metabolite, O-des-methyl-ibogaine, had markedly reduced σ2 affinity relative to ibogaine (Ki = 5,226 nM) and also lacked significant affinity for σ1 sites. (±)-Coronaridine ((±)-18-carbomethoxyibogamine) and harmaline (1-methyl-7-methoxy-3,4-dihydro-β-carboline) lacked significant affinity for either σ subtype. Thus, σ2 receptors could play a role in the actions of ibogaine.

σ Receptor-active neuroleptics are cytotoxic to C6 glioma cells in culture

When exposed to neuroleptics (100 microM), C6 glioma cells exhibited marked changes in cell morphology, accompanied by cessation of cell division and ultimately cell death. The degree of activity generally correlated with binding affinity at sigma sites: fluphenazine = perphenazine = haloperidol = reduced haloperidol > pimozide = spiperone >> >> (-)-sulpiride. Sigma-inactive compounds (100 microM) which block dopamine, serotonin, phencyclidine, muscarinic receptors and adrenoceptors showed no effect. These results may suggest a role of sigma binding sites in maintenance of cell viability.

CB-64D and CB-184: ligands with high σ2 receptor affinity and subtype selectivity

Abstract Four members of a novel class of sigma (σ) ligands were investigated for σ subtype selectivity. (−)-1 S ,5 S - and (+)-1 R ,5 R -( E )-8-Benzylidene-5-(3-hydroxyphenyl)-2-methylmorphan-7-one (CB-64L and CB-64D, respectively) exhibited σ 1 K 1 = 10.5 nM and 3063 nM; σ 2 K i = 154 nM and 16.5 nM, respectively. The corresponding 3,4-dichloro derivatives, (−)-1 S ,5 S - and (+)-1 R ,5 R -( E )-8-(3,4-dichlorobenzylidene)-5-(3-hydroxyphenyl)-2-methylmorphan-7-one (CB-182 and CB-184, respectively) were also examined. CB-182 ((−)-isomer) showed σ 1 and σ 2 K i = 27.3 nM and 35.5 nM, respectively, whereas CB-184 ((+)-isomer) exhibited σ 1 and σ 2 K i = 7436 nM and 13.4 nM, respectively. Thus, the two σ subtypes showed opposite enantioselectivity for these compounds, with (−) > (+) at σ 1 and (+) > (−) at σ 2 . Importantly, CB-64D and CB-184 showed high σ 2 affinity and, respectively, 185-fold and 554-fold selectivity for σ 2 receptors over σ 1 . While high σ 2 selectivity relative to σ 1 was achieved with these compounds, they both exhibited high affinity at mu (μ) opioid receptors ( K i = 37.6 nM and 4.5 nM, respectively). Despite this, CB-64D and CB-184 will be useful tools for further characterization of σ 2 receptors.

Synthesis, in vitro validation and in vivo pharmacokinetics of [125I]N-[2-(4-Iodophenyl)Ethyl]-N-Methyl-2-(1-Piperidinyl) ethylamine: A high-affinity ligand for imaging sigma receptor positive tumors☆

N-[2-(4-iodophenyl)ethyl]-N-methyl-2-(1-piperidinyl)ethylamine, IPEMP, and the corresponding bromo derivative, BrPEMP, have been synthesized and characterized. Both BrPEMP and IPEMP were evaluated for sigma-1 and sigma-2 subtype receptor affinities and found to possess very high affinities for both receptor subtypes. The precursor for radioiodination n-tributylstannylphenylethylpiperidinylethylamine was prepared from its bromo derivative by palladium-catalyzed stannylation reaction. Radioiodinated 4-[125I]PEMP was readily prepared in high yields and high specific activity by oxidative iododestannylation reaction using chloramine-T as oxidizing agent. Sites labeled by 4-[125I]PEMP in guinea pig brain membranes showed high affinity for BD1008, haloperidol, and (+)-pentazocine (Ki = 5.06 +/- 0.40, 32.6 +/- 2.75, and 48.1 +/- 8.60 nM, respectively), which is consistent with sigma receptor pharmacology. Competition binding studies of 4-[125I]PEMP in melanoma (A375) and MCF-7 breast cancer cells showed a high affinity, dose-dependent inhibition of binding with known sigma ligand N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl) ethylamine, BD1008 (Ki = 5, 11 nM, respectively), supporting the labeling of sigma sites in these cells. Haloperidol, however showed a weaker (Ki = 100-200 nM) affinity for the sites labeled by 4-[125I]PEMP in these cells. Biodistribution studies of 4-[125I]PEMP in rats showed a fast clearance of this radiopharmaceutical from blood, liver, lung, and other organs. A co-injection of 4-IPEMP with 4-[125I]PEMP resulted in 37%, 69%, and 35% decrease in activity in liver, kidney, and brain (organs possessing sigma receptors), respectively at 1-h postinjection. These results suggest that 4-[125I]PEMP is a promising radiopharmaceutical for pursuing further studies in animal models with tumors.