Trishomocubanes, a new class of selective and high affinity ligands for the sigma binding site

doi:10.1016/0960-894X(96)00067-4

Bioorganic & Medicinal Chemistry Letters

Volume 6, Issue 6, 19 March 1996, Pages 595-600

https://doi.org/10.1016/0960-894X(96)00067-4 Get rights and content

Abstract

The synthesis, receptor binding, and preliminary structural characterisation of trishomocubanes of types pentacyclo[5.4.0.0^2,6.0^3,10.0^5,9]undecylamines- and 4-azahexacyclo[5.4.1.0^2,6.0^3,10.0^5,9.0^8,11]dodecanes are described. These ligands demonstrated high selectivity and affinity for the sigma binding site.

The synthesis, in vitro receptor binding, and preliminary structural characterisation of trishomocubanes of the type pentacyclo[5.4.0.0^2,6.0^3,10.0^5,9] undecylamines and 4-azahexacyclo[5.4.1.0^2,6.0^3,10.0^5.9.0^8,11]dodecanes are described.

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Cited by (26)

Microwave-assisted methods for the synthesis of pentacyclo[5.4.0.02,6.03,10.05,9]undecylamines
2013, Tetrahedron Letters
Efficient methodologies for the preparation of pentacyclo[5.4.0.0^2,6.0^3,10.0^5,9]undecane (PCU) amine derivatives are described via microwave-assisted synthesis. The obtained results revealed that microwave-assisted synthetic procedures under controlled conditions (power, temperature and time) are very convenient, high yielding, efficient and low-cost methods for the preparation of PCU amine derivatives. The new methods show several advantages including operational simplicity, good performance, significant reduction in reaction time, less by-product formation and easier purification.
N-substituted 8-aminopentacyclo[5.4.0.02,6.03,10. 05,9]undecanes as σ receptor ligands with potential neuroprotective effects
2013, Bioorganic and Medicinal Chemistry
Citation Excerpt :
The obvious structural similarities between 8a, 9a, 10, 11 and various trishomocubanes previously reported by us prompted the systematic investigation of the relationship between structure and inhibitory NOS activity, with the aim of identifying potentially neuroprotective trishomocubanes. We previously reported the σ receptor activity of numerous N-substituted 4-azahexacyclo[5.4.1.02,6.03,10.05,9.08,11]dodecan-3-ols (8, Fig. 3), demonstrating the utility of the trishomocubane framework for developing selective σ receptor ligands.73–76,80–85 Prior structure–affinity relationship (SAfiR) studies in our laboratories have focused on changes to σ receptor binding resulting from isomerization of the hemiaminal group of 8 to the analogous oxa-bridged hemiaminal ether, expansion the trishomocubane cage of 8 to the corresponding adamantane-derived hemiaminal, and steric reduction of 8 to the simplest azabicyclic subunit.72,86,87
Several libraries of similarly N-substituted 8-aminopentacyclo[5.4.0.0^2,6.0^3,10.0^5,9]undecanes (9), N-methyl-8-aminopentacyclo[5.4.0.0^2,6.0^3,10.0^5,9]undecanes (14), and N-methyl-11-aminopentacyclo[5.4.0.0^2,6.0^3,10.0^5,9]undecan-8-ones (13) were synthesised and screened against a panel of CNS targets in order to develop structure–affinity relationships for cage-modified trishomocubane σ receptor ligands based on the N-substituted 4-azahexacyclo[5.4.1.0^2,6.0^3,10.0^5,9.0^8,11]dodecan-3-ol (8) scaffold. In general, compared to the corresponding 4-azahexacyclo[5.4.1.0^2,6.0^3,10.0^5,9.0^8,11]dodecan-3-ols, compounds of type 9 were potent σ receptor ligands with low levels of subtype selectivity, while the corresponding N-methyl-8-aminopentacyclo[5.4.0.0^2,6.0^3,10.0^5,9]undecanes showed reduced affinity but greater selectivity for σ₂ receptors. The N-methyl-11-aminopentacyclo[5.4.0.0^2,6.0^3,10.0^5,9]undecan-8-ones demonstrated the poorest σ receptor affinities, suggesting that 4-azahexacyclo[5.4.1.0^2,6.0^3,10.0^5,9.0^8,11]dodecan-3-ols interact with σ receptors in the bridged hemiaminal form rather than as the non-transannular, aminoketone tautomers. Several compounds of type 8, 9, and 14 were assessed for their ability to inhibit nitric oxide release in vitro, and demonstrated comparable or greater efficacy than 4-phenyl-1-(4-phenylbutyl)piperidine (PPBP), an established neuroprotective σ ligand with NOS inhibitory activity.
3D-QSAR and docking studies of pentacycloundecylamines at the sigma-1 (σ<inf>1</inf>) receptor
2013, Bioorganic and Medicinal Chemistry Letters
Pentacycloundecylamine (PCU) derived compounds have been shown to be promising lead structures for the development of novel drug candidates aimed at a variety of neurodegenerative and psychiatric diseases. Here we show for the first time a 3D quantitative structure–activity relationship (3D-QSAR) for a series of aza-PCU-derived compounds with activity at the sigma-1 (σ₁) receptor. A comparative molecular field analysis (CoMFA) model was developed with a partial least squares cross validated (q²) regression value of 0.6, and a non-cross validated r² of 0.9. The CoMFA model was effective at predicting the sigma-1 activities of a test set with an r² >0.7. We also describe here the docking of the PCU-derived compounds into a homology model of the sigma-1 (σ₁) receptor, which was developed to gain insight into binding of these cage compounds to the receptor. Based on docking studies we evaluated in a [³H]pentazocine binding assay an oxa-PCU, NGP1-01 (IC₅₀ = 1.78 μM) and its phenethyl derivative (IC₅₀ = 1.54 μM). Results from these studies can be used to develop new compounds with specific affinity for the sigma-1(σ₁) receptor.
Oxo-bridged isomers of aza-trishomocubane sigma (σ) receptor ligands: Synthesis, in vitro binding, and molecular modeling
2010, Bioorganic and Medicinal Chemistry Letters
Behavioural effects of trishomocubanes in rats with unilateral 6-hydroxydopamine lesions
2008, Behavioural Brain Research
Whilst dopamine replacement improves cardinal features of Parkinson's disease, chronic levodopa administration is associated with dose-related side effects and not all symptoms are ameliorated, necessitating the development of new treatments. Studies of trishomocubanes, a novel group of sigma ligands, have shown enhanced amphetamine-stimulated striatal release of dopamine and a potentially neuroprotective action in vitro and reversal of reserpine-induced catalepsy in vivo. Such effects warrant investigation in animal models of parkinsonism. Our study therefore examines two novel trishomocubane compounds, N-(3′-fluorophenyl)methyl-4-azahexacyclo[5.4.1.0^2,6.0^3,10.0^5,9.0^8,11]dodecan-3-ol (1) and, N-(3′-fluorophenyl)ethyl-4-azahexacyclo[5.4.1.0^2,6.0^3,10.0^5,9.0^8,11]dodecan-3-ol (2) in the 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease. A variety of motor behaviours were studied in rats given 6-OHDA lesions. Groups of lesioned rats were given either (1) or (2) or vehicle solution i.p. Acute administration of 3 mg/kg (1) resulted in a decrease in locomotor activity. Twenty-five milligrams per kilogram (2) caused a decrease in locomotor activity at t = 10 and t = 20 min of the locomotor test but this was not found when (2) was co-administered with either apomorphine or amphetamine. The decreased locomotor activity indicates that (1) and (2) may have sedative/anxiolytic effect(s). However, elevated plus maze data failed to demonstrate anxiolysis with (2). Quantification of dopaminergic neurons did not demonstrate any significant difference in the magnitude of cell loss between drug-treated vs. vehicle treated rats so no neuroprotective effect was demonstrated in this model at the doses utilised.
Structure-activity relationships of pentacycloundecylamines at the N-methyl-d-aspartate receptor
2007, Bioorganic and Medicinal Chemistry
Prompted by our interest in neuroprotective agents with multiple mechanisms of action, we assessed the structure–activity relationship of a series of pentacycloundecylamine derivatives previously shown to have both L-type calcium channel blocking activity and N-methyl-d-aspartate receptor (NMDAR) antagonistic activity. We utilized a functional assay to measure NMDAR channel block using ⁴⁵Ca²⁺ influx into synaptoneurosomes. The cage amine 8-benzylamino-8,11-oxapentacyclo[5.4.0.0^2,6. 0^3,10.0^5,9]undecane (NPG1-01) proved to be the most potent experimental compound with an IC₅₀ of 2.98 μM, while 8-amino-pentacyclo[5.4.0.0^2,6.0^3,10.0^5,9]undecane had the next most potent IC₅₀ of 4.06 μM. Increasing the polycyclic cage size of NGP1-01 from a pentacycloundecane to a tridecane cage structure, but retaining the N-benzyl moiety decreased potency 10-fold, indicating a limitation on the volume of the cage that can be accommodated in the channel binding site. In the presence of NGP1-01, NMDA/glycine-induced maximal ⁴⁵Ca²⁺ influx was attenuated by 34% with an insignificant effect on agonist potency. These results are consistent with uncompetitive antagonism for this group of compounds. Radioligand binding studies with [³H]MK-801 or [³H]TCP showed little or no displacement of these ligands by pentacycloundecylamines, suggesting that the latter compounds bind to a unique site in the NMDAR channel. The pentacycloundecylamines tested represent a novel group of NMDAR antagonists that have potential as therapeutic agents for neurodegenerative diseases including Parkinson’s and Alzheimer’s disease.

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Bioorganic & Medicinal Chemistry Letters

Abstract

References (17)

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol. [Mol. Pharmacol. Sect.]

Neurosci. Let.

Trends Neurosci.

Eur. J. Med. Chem.

Tetrahedron

Trends Pharm. Sci

Cited by (26)

Microwave-assisted methods for the synthesis of pentacyclo[5.4.0.0<sup>2,6</sup>.0<sup>3,10</sup>.0<sup>5,9</sup>]undecylamines

N-substituted 8-aminopentacyclo[5.4.0.0<sup>2,6</sup>.0<sup>3,10</sup>. 0<sup>5,9</sup>]undecanes as σ receptor ligands with potential neuroprotective effects

3D-QSAR and docking studies of pentacycloundecylamines at the sigma-1 (σ<inf>1</inf>) receptor

Oxo-bridged isomers of aza-trishomocubane sigma (σ) receptor ligands: Synthesis, in vitro binding, and molecular modeling

Behavioural effects of trishomocubanes in rats with unilateral 6-hydroxydopamine lesions

Structure-activity relationships of pentacycloundecylamines at the N-methyl-d-aspartate receptor