RAR and RXR agonists: A collection of pyrazine-based RAR/RXR ligands were prepared by a series of palladium catalyzed cross-coupling reactions and characterized. Structure-activity relationships were elucidated. Retinoic acid receptor (RAR) alpha/beta-subtype-selective and retinoid X receptor (RXR) inverse agonist activities are described for pyrazine acrylic acid arotinoid, 14 d. Heterocyclic arotinoids derived from central-region dihalogenated pyrazine scaffolds have been synthesized by consecutive halogen and/or position-selective palladium-catalyzed cross-coupling reactions. Pyrazines were further functionalized as alkyl ethers or methylamines prior to the last Pd-catalyzed reactions. Transient transactivation studies with the retinoic acid receptor (RAR) alpha, beta, and gamma subtypes and with retinoid X receptor (RXR) alpha revealed distinct agonist, antagonist, and inverse agonist activities for these compounds. Of interest are the RARalpha,beta-selective inverse agonists with pyrazine acrylic acid structures, in particular 14 c, which is RARbeta-selective, and 14 d, a pan-RAR/RXR inverse agonist with more affinity for the RAR subtypes that enhance the interaction of RAR with cognate corepressors.