Synthesis of novel 2-(1-adamantanylcarboxamido)thiophene derivatives. Selective cannabinoid type 2 (CB2) receptor agonists as potential agents for the treatment of skin inflammatory disease

Claudia Mugnaini; Alessandro Rabbito; Antonella Brizzi; Nastasja Palombi; Stefania Petrosino; Roberta Verde; Vincenzo Di Marzo; Alessia Ligresti; Federico Corelli

doi:10.1016/j.ejmech.2018.09.070

Synthesis of novel 2-(1-adamantanylcarboxamido)thiophene derivatives. Selective cannabinoid type 2 (CB2) receptor agonists as potential agents for the treatment of skin inflammatory disease

Eur J Med Chem. 2019 Jan 1:161:239-251. doi: 10.1016/j.ejmech.2018.09.070. Epub 2018 Oct 13.

Authors

Claudia Mugnaini¹, Alessandro Rabbito², Antonella Brizzi³, Nastasja Palombi³, Stefania Petrosino², Roberta Verde², Vincenzo Di Marzo², Alessia Ligresti⁴, Federico Corelli³

Affiliations

¹ Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100, Siena, Italy. Electronic address: claudia.mugnaini@unisi.it.
² Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via dei Campi Flegrei 34, 80078, Pozzuoli (Napoli), Italy.
³ Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100, Siena, Italy.
⁴ Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via dei Campi Flegrei 34, 80078, Pozzuoli (Napoli), Italy. Electronic address: aligresti@icb.cnr.it.

PMID: 30359820
DOI: 10.1016/j.ejmech.2018.09.070

Abstract

A set of CB2R ligands, based on the thiophene scaffold, was synthesized and evaluated in in vitro assays. Compounds 8c-i, k, l, bearing the 3-carboxylate and 2-(adamantan-1-yl)carboxamido groups together with apolar alkyl/aryl substituents at 5-position or at 4- and 5-positions of the thiophene ring possess high CB2R affinity at low nanomolar concentration, good receptor selectivity, and agonistic functional activity. The full agonist 8g, showing the best balance between receptor affinity and selectivity, was tested in vitro in an experimental model of allergic contact dermatitis and proved to be able to block the release of MCP-2 in HaCaT cells at 10 μM concentration.

Keywords: CB2R agonists; CBR ligands; Chemokine release; Skin inflammation.

MeSH terms

Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Cell Line
Cell Survival / drug effects
Dose-Response Relationship, Drug
HEK293 Cells
Humans
Immunosuppressive Agents / chemical synthesis
Immunosuppressive Agents / chemistry
Immunosuppressive Agents / pharmacology*
Inflammation / drug therapy*
Inflammation / pathology
Keratinocytes / drug effects
Molecular Structure
Receptor, Cannabinoid, CB2 / agonists*
Skin Diseases / drug therapy*
Skin Diseases / pathology
Structure-Activity Relationship
Thiophenes / chemical synthesis
Thiophenes / chemistry
Thiophenes / pharmacology*

Substances

Anti-Inflammatory Agents, Non-Steroidal
Immunosuppressive Agents
Receptor, Cannabinoid, CB2
Thiophenes