Rational design, synthesis, and pharmacological properties of new 1,8-naphthyridin-2(1H)-on-3-carboxamide derivatives as highly selective cannabinoid-2 receptor agonists

Clementina Manera; Giuseppe Saccomanni; Barbara Adinolfi; Veronica Benetti; Alessia Ligresti; Maria Grazia Cascio; Tiziano Tuccinardi; Valentina Lucchesi; Adriano Martinelli; Paola Nieri; Emanuela Masini; Vincenzo Di Marzo; Pier Luigi Ferrarini

doi:10.1021/jm801563d

Rational design, synthesis, and pharmacological properties of new 1,8-naphthyridin-2(1H)-on-3-carboxamide derivatives as highly selective cannabinoid-2 receptor agonists

Clementina Manera, Giuseppe Saccomanni, Barbara Adinolfi, Veronica Benetti, Alessia Ligresti, Maria Grazia Cascio, Tiziano Tuccinardi, Valentina Lucchesi, Adriano Martinelli, Paola Nieri, Emanuela Masini, Vincenzo Di Marzo, Pier Luigi Ferrarini

Molecular Cardiology and Membrane Proteins

34 Citations (Scopus)

Abstract

The CB(2) receptor activation can be exploited for the treatment of diseases such as chronic pain and tumors of immune origin, devoid of psychotropic activity. On the basis of our already reported 1,8-naphthyridin-4(1H)-on-3-carboxamide derivatives, new 1,8-naphthyridin-2(1H)-on-3-carboxamide derivatives were designed, synthesized, and tested for their affinities toward the human CB(1) and CB(2) cannabinoid receptors. Some of the reported compounds showed a subnanomolar CB(2) affinity with a CB(1)/CB(2) selectivity ratio greater than 200 (compounds 6, 12, cis-12, 13, and cis-13). Further studies revealed that compound 12, which presented benzyl and carboxy-4-methylcyclohexylamide substituents bound in the 1 and 3 positions, exerted a CB(2)-mediated inhibitory action on immunological human basophil activation. On the human T cell leukemia line Jurkat the same derivative induced a concentration-dependent decrease of cell viability. The obtained results suggest that 1,8-naphthyridin-2(1H)-on-3-carboxamides represent a new scaffold very suitable for the development of new promising CB(2) agonists.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	52
Issue number	12
Pages (from-to)	3644-51
Number of pages	7
ISSN	0022-2623
DOIs	https://doi.org/10.1021/jm801563d
Publication status	Published - 2009

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Manera, C., Saccomanni, G., Adinolfi, B., Benetti, V., Ligresti, A., Cascio, M. G., Tuccinardi, T., Lucchesi, V., Martinelli, A., Nieri, P., Masini, E., Di Marzo, V., & Ferrarini, P. L. (2009). Rational design, synthesis, and pharmacological properties of new 1,8-naphthyridin-2(1H)-on-3-carboxamide derivatives as highly selective cannabinoid-2 receptor agonists. Journal of Medicinal Chemistry, 52(12), 3644-51. https://doi.org/10.1021/jm801563d

Rational design, synthesis, and pharmacological properties of new 1,8-naphthyridin-2(1H)-on-3-carboxamide derivatives as highly selective cannabinoid-2 receptor agonists. / Manera, Clementina; Saccomanni, Giuseppe; Adinolfi, Barbara et al.

In: Journal of Medicinal Chemistry, Vol. 52, No. 12, 2009, p. 3644-51.

Research output: Contribution to journal › Journal article › Research › peer-review

Manera, C, Saccomanni, G, Adinolfi, B, Benetti, V, Ligresti, A, Cascio, MG, Tuccinardi, T, Lucchesi, V, Martinelli, A, Nieri, P, Masini, E, Di Marzo, V & Ferrarini, PL 2009, 'Rational design, synthesis, and pharmacological properties of new 1,8-naphthyridin-2(1H)-on-3-carboxamide derivatives as highly selective cannabinoid-2 receptor agonists', Journal of Medicinal Chemistry, vol. 52, no. 12, pp. 3644-51. https://doi.org/10.1021/jm801563d

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title = "Rational design, synthesis, and pharmacological properties of new 1,8-naphthyridin-2(1H)-on-3-carboxamide derivatives as highly selective cannabinoid-2 receptor agonists",

abstract = "The CB(2) receptor activation can be exploited for the treatment of diseases such as chronic pain and tumors of immune origin, devoid of psychotropic activity. On the basis of our already reported 1,8-naphthyridin-4(1H)-on-3-carboxamide derivatives, new 1,8-naphthyridin-2(1H)-on-3-carboxamide derivatives were designed, synthesized, and tested for their affinities toward the human CB(1) and CB(2) cannabinoid receptors. Some of the reported compounds showed a subnanomolar CB(2) affinity with a CB(1)/CB(2) selectivity ratio greater than 200 (compounds 6, 12, cis-12, 13, and cis-13). Further studies revealed that compound 12, which presented benzyl and carboxy-4-methylcyclohexylamide substituents bound in the 1 and 3 positions, exerted a CB(2)-mediated inhibitory action on immunological human basophil activation. On the human T cell leukemia line Jurkat the same derivative induced a concentration-dependent decrease of cell viability. The obtained results suggest that 1,8-naphthyridin-2(1H)-on-3-carboxamides represent a new scaffold very suitable for the development of new promising CB(2) agonists.",

author = "Clementina Manera and Giuseppe Saccomanni and Barbara Adinolfi and Veronica Benetti and Alessia Ligresti and Cascio, {Maria Grazia} and Tiziano Tuccinardi and Valentina Lucchesi and Adriano Martinelli and Paola Nieri and Emanuela Masini and {Di Marzo}, Vincenzo and Ferrarini, {Pier Luigi}",

note = "Keywords: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Design; Drug Evaluation, Preclinical; Humans; Jurkat Cells; Models, Molecular; Molecular Structure; Naphthyridines; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Structure-Activity Relationship",

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doi = "10.1021/jm801563d",

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AU - Manera, Clementina

AU - Saccomanni, Giuseppe

AU - Adinolfi, Barbara

AU - Benetti, Veronica

AU - Ligresti, Alessia

AU - Cascio, Maria Grazia

AU - Tuccinardi, Tiziano

AU - Lucchesi, Valentina

AU - Martinelli, Adriano

AU - Nieri, Paola

AU - Masini, Emanuela

AU - Di Marzo, Vincenzo

AU - Ferrarini, Pier Luigi

N1 - Keywords: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Design; Drug Evaluation, Preclinical; Humans; Jurkat Cells; Models, Molecular; Molecular Structure; Naphthyridines; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Structure-Activity Relationship

PY - 2009

Y1 - 2009

N2 - The CB(2) receptor activation can be exploited for the treatment of diseases such as chronic pain and tumors of immune origin, devoid of psychotropic activity. On the basis of our already reported 1,8-naphthyridin-4(1H)-on-3-carboxamide derivatives, new 1,8-naphthyridin-2(1H)-on-3-carboxamide derivatives were designed, synthesized, and tested for their affinities toward the human CB(1) and CB(2) cannabinoid receptors. Some of the reported compounds showed a subnanomolar CB(2) affinity with a CB(1)/CB(2) selectivity ratio greater than 200 (compounds 6, 12, cis-12, 13, and cis-13). Further studies revealed that compound 12, which presented benzyl and carboxy-4-methylcyclohexylamide substituents bound in the 1 and 3 positions, exerted a CB(2)-mediated inhibitory action on immunological human basophil activation. On the human T cell leukemia line Jurkat the same derivative induced a concentration-dependent decrease of cell viability. The obtained results suggest that 1,8-naphthyridin-2(1H)-on-3-carboxamides represent a new scaffold very suitable for the development of new promising CB(2) agonists.

AB - The CB(2) receptor activation can be exploited for the treatment of diseases such as chronic pain and tumors of immune origin, devoid of psychotropic activity. On the basis of our already reported 1,8-naphthyridin-4(1H)-on-3-carboxamide derivatives, new 1,8-naphthyridin-2(1H)-on-3-carboxamide derivatives were designed, synthesized, and tested for their affinities toward the human CB(1) and CB(2) cannabinoid receptors. Some of the reported compounds showed a subnanomolar CB(2) affinity with a CB(1)/CB(2) selectivity ratio greater than 200 (compounds 6, 12, cis-12, 13, and cis-13). Further studies revealed that compound 12, which presented benzyl and carboxy-4-methylcyclohexylamide substituents bound in the 1 and 3 positions, exerted a CB(2)-mediated inhibitory action on immunological human basophil activation. On the human T cell leukemia line Jurkat the same derivative induced a concentration-dependent decrease of cell viability. The obtained results suggest that 1,8-naphthyridin-2(1H)-on-3-carboxamides represent a new scaffold very suitable for the development of new promising CB(2) agonists.

U2 - 10.1021/jm801563d

DO - 10.1021/jm801563d

M3 - Journal article

C2 - 19435366

SN - 0022-2623

VL - 52

SP - 3644

EP - 3651

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 12

ER -

Rational design, synthesis, and pharmacological properties of new 1,8-naphthyridin-2(1H)-on-3-carboxamide derivatives as highly selective cannabinoid-2 receptor agonists

Abstract

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