.sigma. Ligands with Subnanomolar Affinity and Preference for the .sigma.2 Binding Site. 2. Spiro-Joined Benzofuran, Isobenzofuran, and Benzopyran Piperidines

Abstract

Spiro[isobenzofuran-1(3H),4'-piperidines] and the corresponding benzofuran and benzopyran derivatives have been synthesized and evaluated as sigma ligands. The compounds are related to Lu 28-179 (1'-[4-[1-(4-fluorophenyl)-1H-indol-3-yl]-1- butyl]spiro[isobenzofuran-1(3H),4'-piperidine]) that has been demonstrated to be a selective sigma 2 ligand with affinity in the subnanomolar range. The object of the study was to determine the structural factors governing sigma 1/sigma 2 affinity and selectivity within this class of compounds. The N-substituent in spiro[isobenzofuran-1(3H),4'-piperidines] is highly important, both for affinity and selectivity. Spiropiperidines with no or small N-substituents (H, Me, Et) exert very low affinity for both sigma 1 and sigma 2 binding sites (IC50(sigma 1, sigma 2) > 100 nM), whereas medium-sized substituents (e.g., Pr, Bu, Ph(CH2)2) result in potent, but unselective compounds (IC50(sigma 1, sigma 2) = 2-5 nM). Increasing the chain length and the lipophilicity of the N-substituent result in compounds in which high affinity for sigma 2 binding sites is retained and with selectivity for sigma 2 vs sigma 1 binding sites (e.g., 4-cyclohexyl-1-butyl: IC50-(sigma 1) = 1.5 nM, IC50(sigma 2) = 0.07 nM). Introduction of substituents in the benzene ring of the spiro[isobenzofuran-1(3H),4'-piperidine] ring system of Lu 28-179 mainly affects affinity for sigma 1 binding sites. Compounds with substituents (F, CF3) in the 4- or 7-position of the isobenzofuran display high affinity for sigma 2 binding sites (IC50(sigma 2) = 0.5-2 nM) and very low affinity for sigma 1 binding sites (IC50(sigma 1) > 100 nM). Compounds with substituents (F, CF3, Me) in the 5- or 6-position of the isobenzofuran exert increased affinity for sigma 1 binding sites (IC50(sigma 1) = 5-30 nM, IC50(sigma 2) = 0.3-7 nM), thus rendering unselective compounds. Exchanging the isobenzofuran moiety of Lu 28-179 with thioisobenzofuran, benzofuran, or benzopyran also has a pronounced effect on both affinity and selectivity for sigma binding sites. The position of the oxygen atom and the position of the spiroconnection with the 4-position of the piperidine ring were varied, and only compounds in which both the benzene ring and the heteroatom are attached directly to the piperidine ring retain high affinity and selectivity for sigma 2 binding sites (e.g., 3,4-dihydro-1'-[4-[1-(4-fluorophenyl)-1H-indol-3-yl]-1- butyl]spiro[1H-2-benzopyran-1,4'-piperidine]: IC50(sigma 1) = 53 nM, IC50(sigma 2) = 0.9 nM).(ABSTRACT TRUNCATED AT 400 WORDS)

Steroids ModulateN-Methyl-D-aspartate-Stimulated [3H]Dopamine Release from Rat Striatum via σ Receptors

“…The inhibition of NMDA-stimulated [ 3 H]dopamine release by 1 M progesterone and 3 M pregnenolone was fully reversed by the 1 antagonist DuP734 (K i ϭ 10 nM) (Culp et al, 1992) at 100 nM and the 2 antagonist Lu28-179 (K i ϭ 0.12 nM) (Moltzen et al, 1995) at 1 nM. The reversal seen by 100 nM DuP734 was somewhat above control, although associated with a relatively high error determination.…”

Sigma receptors: biology and therapeutic potential

“…Interestingly, most sigma agonists produce bell-shaped dose-response curves on the NMDA-induced effect (Couture and Debonnel 1998), and this has been suggested to be due to the recruitment of different subtypes of sigma receptors at higher doses (Bergeron and Debonnel 1997). Administration of the new selective sigma-2 ligand Lu 28-179 (Moltzen et al 1995) dose dependently potentiated the NMDA response in the CA3 region of rat hippocampus, whereas ibogaine, a sigma-2 ligand with moderate affinity for the receptor (Bowen et al 1995b), slightly increased the NMDA response (Couture and Debonnel 1998). To explain such differences, it has been proposed that several sigma-2 receptor subtypes may exist (Couture and Debonnel 1998).…”

Synthesis and Structure−Activity Relationships of 1-Aralkyl-4-Benzylpiperidine and 1-Aralkyl-4-Benzylpiperazine Derivatives as Potent σ Ligands

“…Spiro [2]benzopyran-1,4′-piperidine 5 (Chart 1) is the most potent and σ 2 selective ligand described so far (σ 1 , IC 50 ) 53 nM; σ 2 , IC 50 ) 0.90 nM). 8 There is great interest in the development of selective σ 2 ligands: it appears that this receptor subtype is involved in regulation of cell proliferation and maintenance of cell viability, suggesting a therapeutic use as novel antineoplastic agents. Moreover, σ 2 receptor antagonists have been demonstrated to limit the motor extrapyramidal side effects caused by typical antipsychotic agents.…”