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October 18, 2023
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4-Aryl-1-oxa-4,9-diazaspiro[5.5]undecane Derivatives as Dual ?-Opioid Receptor Agonists and ?1 Receptor Antagonists for the Treatment of Pain

Publicated to: Journal Of Medicinal Chemistry. 63 (5): 2434-2454 - 2020-03-12 63(5), DOI: 10.1021/acs.jmedchem.9b01256

Authors:

Garcia, Monica; Virgili, Marina; Alonso, Monica; Alegret, Caries; Fernandez, Begona; Port, Adriana; Pascual, Rosalia; Monroy, Xavier; Vidal-Torres, Alba; Serafini, Maria-Teresa; Miguel Vela, Jose; Almansa, Carmen
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Affiliations

Enantia SL, Caner Baldiri Reixac,10 Parc Cient Barcelona, Barcelona 08028, Spain - Author
ESTEVE Pharmaceut SA, Drug Discovery & Preclin Dev, Carrer Baldiri Reixac,4-8 Parc Cient Barcelona, Barcelona 08028, Spain - Author

Abstract

The synthesis and pharmacological activity of a new series of 1-oxa-4,9-diazaspiro[5.5]undecane derivatives as potent dual ligands for the sigma-1 receptor (sigma R-1) and the mu-opioid receptor (MOR) are reported. The different positions of the central scaffold, designed using a merging strategy of both target pharmacophores, were explored using a versatile synthetic approach. Phenethyl derivatives in position 9, substituted pyridyl moieties in position 4 and small alkyl groups in position 2 provided the best profiles. One of the best compounds, 15au, showed a balanced dual profile (i.e., MOR agonism and sigma antagonism) and a potent analgesic activity, comparable to the MOR agonist oxycodone in the paw pressure test in mice. Contrary to oxycodone, as expected from the addition of sigma R-1 antagonism, 15au showed local, peripheral activity in this test, which was reversed by the sigma R-1 agonist PRE-084. At equianalgesic doses, 15au showed less constipation than oxycodone, providing evidence that dual MOR agonism and sigma R-1 antagonism may be a useful strategy for obtaining potent and safer analgesics.
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Keywords

AlkaneAlkanesAnalgesiaAnalgesic activityAnalgesic agentAnalgesicsAnalgesics, opioidAnimalAnimal experimentAnimal modelAnimalsAntinociceptionArticleAryl 1 oxa 4,9 diazaspiro[5.5]undecane derivativeBindingBivalent ligandsChemistryConstipationDesignDiscoveryFemaleHumanHumansMaleMetabolismMiceModelsModels, molecularMolecular modelMouseMu opiate receptorMu opiate receptor agonistNarcotic analgesic agentNonhumanOxycodonePainPain managementPredictionProteinReceptors, opioid, muReceptors, sigmaS1raSigma 1 opiate receptorSigma opiate receptorSigma receptor antagonistSigma-1 receptorSpiro compoundSpiro compoundsStrategiesUnclassified drugUndecane

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Journal Of Medicinal Chemistry due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2020, it was in position 3/62, thus managing to position itself as a Q1 (Primer Cuartil), in the category Chemistry, Medicinal. Notably, the journal is positioned above the 90th percentile.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 1.54. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 13, 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2026-01-21, the following number of citations:

  • WoS: 29
  • Scopus: 24
  • Europe PMC: 8
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Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2026-01-21:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 38.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 38 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 6.
  • The number of mentions on the social network X (formerly Twitter): 5 (Altmetric).
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Awards linked to the item

We thank Ma Magdalena Bordas, Raquel Enrech, Joan Andreu Morato ', Mo ' nica Carro, Edmundo Ortega, Ine ' s Alvarez, Pilar Perez, Javier Burguen~o, Marta Pujol, Enrique Hernandez, Javier Farre, Eva Ayet, Raquel Ferna ' ndez-Reinoso, Sandra Yeste, Georgia Gris, Carmen Segale ' s, Bertrand Aubel, Alicia Pardo, and Daniel Zamanillo for their expert contribution to analytical, in vitro and in vivo studies, and Carlos Pe ' rez and Eduardo Villarroel for their contribution to compound management. This work was a part of activities in R&D projects IDI20130943 and IDI20150915, supported by the Spanish Ministerio de Economi ' a y Competitividad (MINECO), through the Centro para el Desarrollo Tecnolo ' gico Industrial (CDTI), cofinanced by the European Union through the European Regional Development Fund (ERDF; Fondo Europeo de Desarrollo Regional, FEDER).
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