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GPR55 is an orphan G-protein coupled receptor involved in various pathophysiological conditions. However, there are only a few noncannabinoid GPR55 ligands reported so far. The lack of potent and selective GPR55 ligands precludes a deep exploration of this receptor. The studies presented here focused on a thienopyrimidine scaffold based on the GPR55 antagonist ML192, previously discovered by high-throughput screening. The GPR55 activities of the new synthesized compounds were assessed using β-arrestin recruitment assays in Chinese hamster ovary cells overexpressing human GPR55. Some derivatives were identified as GPR55 antagonists with functional efficacy and selectivity versus CB1 and CB2 cannabinoid receptors., M.E.A., P.H.R., and N.J. are supported by National Institutes of Health grant R01 DA0455698. M.E.A. and P.Z. thank the financial support NIH P30 DA013429. P.M. and N.J. are supported by the Ministry of Science, Innovation, and Universities, Spain (MCIU)/FEDER grant RTI2018-095544-B-I00 and the Spanish National Research Council (CSIC) grant PIE-201580E033. P.M. acknowledges the Comunidad de Madrid (CM) programme “Atraccion de Talento” number 2018-T2/BMD-10819 and “Juan de la Cierva Incorporación Programme-MICIU” (IJC 2019-042182-I)

Dienoic acids and pentadienyl alcohols are coupled in a decarboxylative and dehydrative manner at ambient temperature using Pd(0) catalysis to generate 1,3,6,8-tetraenes. Contrary to related decarboxylative coupling reactions, an anion-stabilizing group is not required adjacent to the carboxyl group. Of mechanistic importance, it appears that both the diene of the acid and the diene of the alcohol are required for this reaction. To further understand this reaction, substitutions at every unique position of both coupling partners was examined and two potential mechanisms are presented.