Design, synthesis and pharmacological evaluation of spirocyclic σ1 receptor ligands with exocyclic amino moiety (increased distance 1)

Rack, Elisabeth; Fröhlich, Roland; Schepmann, Dirk; Wünsch, Bernhard

doi:10.1016/j.bmc.2011.04.002

Cited by 21 publications

(34 citation statements)

References 58 publications

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“…This result is explained by an increased conformational flexibility around the amino moiety and its substituents. Moreover, the distance of the pharmacophoric elements as suggested by some of the models is not the only factor determining strong ligand 1 receptor interactions [30].…”

Section: Ligands Based On Pharmacophore Modelsmentioning

confidence: 99%

Pharmacophore Models and Development of Spirocyclic Ligands for σ1 Receptors

Wünsch

2012

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The existing pharmacophore models for 1 receptor ligands are summarized. A common feature of these models is a basic amino group surrounded by different hydrophobic structural elements. The development of novel spirocyclic σ1 receptor ligands (e.g. 3, 4) is based on these models. Enlargement of the distance between the basic amino group and the "Primary Hydrophobic Region " by attachment of the amino group at the cyclohexane ring (9, 10) did not lead to increased σ1 affinity. However, introduction of an additional aryl moiety (12, 17) resulted in very potent σ1 receptor ligands. The high affinity of these compounds is explained by interaction of the additional aryl moiety with a previously unrecognized hydrophobic pocket of the σ1 receptor protein. The promising σ1 affinity and selectivity of the spirocyclic piperidine 3 led to the fluorinated PET-tracers [18F]18 and [18F]19 with excellent σ1 receptor affinity, receptor selectivity, pharmacokinetic and neuroimaging properties.

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Section: Ligands Based On Pharmacophore Modelsmentioning

confidence: 99%

Pharmacophore Models and Development of Spirocyclic Ligands for σ1 Receptors

Wünsch

2012

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“…and cyclohexanamines 11 [34] and 13 with 2‐benzopyran and 2‐benzofuran scaffold. a) 5 steps; [35] b) 7 steps; [34] c) 4 steps; [36] d) 4 steps; [37,38] e) NH 4 HCO 2 , Pd/C, CH 3 OH, 17–21 h, 65 °C; trans ‐ 13 , 86 %, cis ‐ 13 , 66 %.…”

Section: Resultsmentioning

confidence: 99%

“…[34]. Transfer hydrogenolysis using NH 4 HCO 2 in the presence of Pd/C converted trans ‐ and cis ‐configured benzylamines trans ‐ 9 and cis ‐ 9 [37,38] into the diastereomeric primary amines trans ‐ 13 and cis ‐ 13 . The secondary amine 6,7‐dimethoxy‐1,2,3,4‐tetrahydroisoquinoline HCl ( 14 HCl) was commercially available (Scheme 1).…”

Section: Resultsmentioning

confidence: 99%

Synthesis of σ Receptor Ligands with a Spirocyclic System Connected with a Tetrahydroisoquinoline Moiety via Different Linkers

2021

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With the aim to develop new σ2 receptor ligands, spirocyclic piperidines or cyclohexanamines with 2‐benzopyran and 2‐benzofuran scaffolds were connected to the 6,7‐dimethoxy‐1,2,3,4‐tetrahydroisoquinoline moiety by variable linkers. In addition to flexible alkyl chains, linkers containing an amide as functional group were synthesized. The 2‐benzopyran and 2‐benzofuran scaffold of the spirocyclic compounds were synthesized from 2‐bromobenzaldehyde. The amide linkers were constructed by acylation of amines with chloroacetyl chloride and subsequent nucleophilic substitution, the alkyl linkers were obtained by LiAlH4 reduction of the corresponding amides. For the development of σ2 receptor ligands, the spirocyclic 2‐benzopyran scaffold is more favorable than the ring‐contracted 2‐benzofuran system. Compounds bearing an alkyl chain as linker generally show higher σ affinity than acyl linkers containing an amide as functional group. A higher σ1 affinity for the cis‐configured cyclohexanamines than for the trans‐configured derivatives was found. The highest σ2 affinity was observed for cis‐configured spiro[[2]benzopyran‐1,1′‐cyclohexan]‐4′‐amine connected to the tetrahydroisoquinoline system by an ethylene spacer (cis‐31, Ki (σ2)=200 nM; the highest σ1 affinity was recorded for the corresponding 2‐benzofuran derivative with a CH2C=O linker (cis‐29, Ki (σ1)=129 nM).

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“…The spirocyclic 2-benzopyrans with af luorine atom or af luoroethoxym oiety at the 5-or 8-positions were synthesized according to unsubstituted 2-benzopyrans (Scheme 2, R 1 = R 2 = H). [17] At first, aW ittig reaction of benzaldehydes 10 a-d with different substituentsa tthe 3-and 6-positions using (methoxymethyl)triphenylphosphonium chloride and KOtBu afforded the enol ethers 11 a-d as mixtures of diastereomers (Scheme 2). For enol ethers 11 b and 11 d with a proton adjacent to the methoxyvinyl moiety (R 1 = H), the ratio of E-t oZ-configured diastereomers was 50:50.…”

Section: Synthesismentioning

confidence: 99%

“…Similar resultsw ere obtained by methylation of fluorinated amines cis-28 e and cis-28 c.T he resulting tertiary amines cis-31 and cis-30 bind with high affinity to both s receptors, but show as light preference for the s 1 subtype.S imilar findings have been describedf or the methylation of various benzylamine derivatives. [17] However,i ntroduction of the larger fluoroethyl moiety (cis-32)d ecreased the affinity for both s receptors.…”

Section: Affinitydatamentioning

confidence: 99%

Structure–Affinity Relationships of Fluorinated Spirocyclic σ₂ Receptor Ligands with an Exocyclic Benzylamino Moiety

et al. 2019

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To identify a potent and selective σ2 receptor ligand appropriate for development as a positron emission tomography (PET) tracer, several fluorinated analogues of the spirocyclic lead compounds trans‐ and cis‐6 (N‐(2,4‐dimethylbenzyl)‐3‐methoxy‐3,4‐dihydrospiro[[2]benzopyran‐1,1′‐cyclohexan]‐4′‐amine) were designed. In multistep syntheses, a fluorine atom was introduced directly or as a 2‐fluoroethoxy moiety on the 2‐benzopyran scaffold, on the dimethylbenzylamino moiety, or on the central amino moiety. The σ1 and σ2 receptor affinity was determined in receptor binding studies with radioligands. With respect to σ2 affinity and σ2/σ1 selectivity, cis‐N‐(2,4‐dimethylbenzyl)‐5‐fluoro‐3‐methoxy‐3,4‐dihydrospiro[[2]benzopyran‐1,1′‐cyclohexan]‐4′‐amine (cis‐15 c, Ki(σ2)=51 nm) and cis‐N‐[4‐(fluoromethyl)‐2‐methylbenzyl]‐3‐methoxy‐3,4‐dihydrospiro[[2]benzopyran‐1,1′‐cyclohexan]‐4′‐amine (cis‐28 e, Ki(σ2)=57 nm) are the most promising ligands. The combination of both structural elements in one molecule, cis‐N‐[4‐(fluoromethyl)‐2‐methylbenzyl]‐5‐fluoro‐3‐methoxy‐3,4‐dihydrospiro[[2]benzopyran‐1,1′‐cyclohexan]‐4′‐amine (cis‐28 c: Ki(σ2)=874 nm), resulted in decreased σ2 and σ1 affinity. Methylation of secondary amines led to three tertiary methylamines with moderate affinity for both σ receptor subtypes.

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Design, synthesis and pharmacological evaluation of spirocyclic σ1 receptor ligands with exocyclic amino moiety (increased distance 1)

Cited by 21 publications

References 58 publications

Pharmacophore Models and Development of Spirocyclic Ligands for σ1 Receptors

Pharmacophore Models and Development of Spirocyclic Ligands for σ1 Receptors

Synthesis of σ Receptor Ligands with a Spirocyclic System Connected with a Tetrahydroisoquinoline Moiety via Different Linkers

Structure–Affinity Relationships of Fluorinated Spirocyclic σ₂ Receptor Ligands with an Exocyclic Benzylamino Moiety

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Design, synthesis and pharmacological evaluation of spirocyclic σ1 receptor ligands with exocyclic amino moiety (increased distance 1)

Cited by 21 publications

References 58 publications

Pharmacophore Models and Development of Spirocyclic Ligands for &#x3C3;1 Receptors

Pharmacophore Models and Development of Spirocyclic Ligands for &#x3C3;1 Receptors

Synthesis of σ Receptor Ligands with a Spirocyclic System Connected with a Tetrahydroisoquinoline Moiety via Different Linkers

Structure–Affinity Relationships of Fluorinated Spirocyclic σ2 Receptor Ligands with an Exocyclic Benzylamino Moiety

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Pharmacophore Models and Development of Spirocyclic Ligands for σ1 Receptors

Pharmacophore Models and Development of Spirocyclic Ligands for σ1 Receptors

Structure–Affinity Relationships of Fluorinated Spirocyclic σ₂ Receptor Ligands with an Exocyclic Benzylamino Moiety