8-(Heteroaryl)phenalkyl-1-Phenyl-1,3,8-triazaspiro[4.5]decan-4-ones as Opioid Receptor Modulators

Jordan, Alfonzo D.; Orsini, Michael J.; Middleton, Steven A.; Connolly, Peter J.; Brenneman, Douglas E.; Pan, Kevin; Reitz, Allen B.

doi:10.2174/157340605774598207

Cited by 5 publications

(4 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For this purpose, 3-bromobenzaldehyde was subjected to a Suzuki cross-coupling 26 reaction with the appropriate boronic acids to yield the known aldehydes VIa-d in a single step. 17, [27][28][29][30] Finally, the pyridine analogue of VIg (i.e., VIj) was prepared as outlined in Scheme 4. 31 Addition of the Grignard reagent derived from 1,4-dibromobutane 32 on 3-bromo-5-ethylnicotinate followed by dehydration of the resulting tertiary alcohol gave the derivative V. The aldehyde function was then installed via bromine-lithium exchange and trapping of the aryllithium with N-formylmorpholine.…”

Section: Chemistrymentioning

confidence: 99%

See 1 more Smart Citation

Towards a New Generation of Potential Antipsychotic Agents Combining D₂ and 5-HT_1A Receptor Activities

et al. 2007

View full text Add to dashboard Cite

We report the discovery and the synthesis of novel, potential antipsychotic compounds combining potent dopamine D2 receptor antagonist and serotonin 5-HT1A receptor agonist properties in the same molecule. We describe the structure-activity relationship that lead us to the promising derivative: N-[(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)ethyl]-3-(cyclopent-1-enyl)-benzylamine 16. The latter has high affinity for D2 and 5-HT1A receptors, whereas it possesses only a weak affinity for 5-HT2A sites. In cellular models of signal transduction, 16 behaves as a silent antagonist at rD2 receptors while activating h5-HT1A receptors with an efficacy at least equivalent to that of the prototypical 5-HT1A agonist (+/-)-8-OH-DPAT. These dual actions confer a unique pharmacological profile to the product. In a behavioral model predictive of positive symptoms, 16 has an activity comparable to that of the typical antipsychotic haloperidol, while it is devoid of cataleptogenic effects. Although it produces behaviors characteristic of 5-HT1A receptor activation in rats, these occur at doses 100 times higher than those with (+/-)-8-OH-DPAT. We believe that the relative balance of D2 and 5-HT1A actions in 16 is appropriate, possibly optimal, to ensure superior efficacy and tolerability over existing antipychotic drugs.

show abstract

Section: Chemistrymentioning

confidence: 99%

“…The aromatic substituents of interest (i.e., R 1 = Ph, thienyl, or furyl) were incorporated by a palladium-catalyzed reaction (Method C). For this purpose, 3-bromobenzaldehyde was subjected to a Suzuki cross-coupling 26 reaction with the appropriate boronic acids to yield the known aldehydes VIa − d in a single step. ,− …”

Section: Chemistrymentioning

confidence: 99%

Towards a New Generation of Potential Antipsychotic Agents Combining D₂ and 5-HT_1A Receptor Activities

et al. 2007

View full text Add to dashboard Cite

show abstract

“…The known 2-(thiophen-2-yl)benzaldehyde (1a) [17], 2-(thiophen-3-yl)benzaldehyde (1b) [18], 2-(furan-3-yl)benz-aldehyde (1c) [19] and 2-(pyridin-4-yl)benzaldehyde (1d) [20] were prepared from commercially available 2-formylphenyl-boronic acid with 2-bromo-, 3-bromothiophene, 3-bromofuran and 4-bromopyridine by Suzuki reaction according to the literature procedure.…”

Section: Methodsmentioning

confidence: 99%

“…The resulting mixture was chromatographed on silica gel eluting with hexane/ethyl acetate (6:1) to produce 0. 18 …”

mentioning

confidence: 99%

Synthesis of 4H‐indeno[1,2‐b]thiophenes, 8H‐indeno[2,1‐b]‐thiophenes and 8H‐indeno[2,1‐b]furans having acrylic acid unit

Jeon

Lee

2008

Journal of Heterocyclic Chem

View full text Add to dashboard Cite

Insights into subtype selectivity of opioid agonists by ligand-based and structure-based methods

Liu

Zhang

et al. 2010

J Mol Model

View full text Add to dashboard Cite

To probe the selective mechanism of agonists binding to three opioid receptor subtypes, ligand-based and receptor-based methods were implemented together and subtype characteristics of opioid agonists were clearly described. Three pharmacophore models of opioid agonists were generated by the Catalyst/HypoGen program. The best pharmacophore models for μ, δ and κ agonists contained four, five and five features, respectively. Meanwhile, the three-dimensional structures of three receptor subtypes were modeled on the basis of the crystal structure of β2-adrenergic receptor, and molecular docking was conducted further. According to these pharmacophore models and docking results, the similarities and differences among agonists of three subtypes were identified. μ or δ agonists, for example, could form one hydrogen bond separately with Tyr129 and Tyr150 at TMIII, whereas κ ones formed a π-π interaction in that place. These findings may be crucial for the development of novel selective analgesic drugs.

show abstract

8-(Heteroaryl)phenalkyl-1-Phenyl-1,3,8-triazaspiro[4.5]decan-4-ones as Opioid Receptor Modulators

Cited by 5 publications

References 0 publications

Towards a New Generation of Potential Antipsychotic Agents Combining D₂ and 5-HT_1A Receptor Activities

Towards a New Generation of Potential Antipsychotic Agents Combining D₂ and 5-HT_1A Receptor Activities

Synthesis of 4H‐indeno[1,2‐b]thiophenes, 8H‐indeno[2,1‐b]‐thiophenes and 8H‐indeno[2,1‐b]furans having acrylic acid unit

Insights into subtype selectivity of opioid agonists by ligand-based and structure-based methods

Contact Info

Product

Resources

About

8-(Heteroaryl)phenalkyl-1-Phenyl-1,3,8-triazaspiro[4.5]decan-4-ones as Opioid Receptor Modulators

Cited by 5 publications

References 0 publications

Towards a New Generation of Potential Antipsychotic Agents Combining D2 and 5-HT1A Receptor Activities

Towards a New Generation of Potential Antipsychotic Agents Combining D2 and 5-HT1A Receptor Activities

Synthesis of 4H‐indeno[1,2‐b]thiophenes, 8H‐indeno[2,1‐b]‐thiophenes and 8H‐indeno[2,1‐b]furans having acrylic acid unit

Insights into subtype selectivity of opioid agonists by ligand-based and structure-based methods

Contact Info

Product

Resources

About

Towards a New Generation of Potential Antipsychotic Agents Combining D₂ and 5-HT_1A Receptor Activities

Towards a New Generation of Potential Antipsychotic Agents Combining D₂ and 5-HT_1A Receptor Activities