The GABAB receptor positive allosteric modulator COR659: In vitro metabolism, in vivo pharmacokinetics in rats, synthesis and pharmacological characterization of metabolically protected derivatives

•COR659, a GABAB PAM, suppresses alcohol and chocolate self-administration in rats.•The methyl ester at C-3 of thiophene is a major site of in vivo metabolic liability.•A panel of 3-substituted COR analogues was studied in vitro and in vivo.•Branched alkyl substituents on the ester group improved in vitro metabolic stability.•An alkyl ester group at C-3 is required for the “anti-alcohol” effects.