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Significantly higher BBB permeability for linear vs. cyclic enkephalin analogs.Nanomolar μ-opioid receptor affinity for the four enkephalin analogs.Significanlty higher antinociception for NMe- vs. S-enkephalin analogs.Enkephalins are active in regulation of nociception in the body and are key in development of new synthetic peptide analogs that target centrally located opioid receptors. In this study, we investigated the in vivo blood–brain barrier (BBB) penetration behavior and antinociceptive activity of two cyclic enkephalin analogs with a thiourea (CycS) or a N-methyl-guanidine bridge (CycNMe), and their linear counterparts (LinS and LinNMe) in mice, as well as their in vitro metabolic stability. 125I-LinS had the highest blood–brain clearance (K1 = 3.46 μL/g min), followed by 125I-LinNMe, 125I-CycNMe, and 125I-CycS (K1 = 1.64, 0.31, and 0.11 μL/g min, respectively). Also, these peptides had a high metabolic stability (t1/2 > 1 h) in mouse serum and brain homogenate, and half-inhibition constant (Ki) values in the nanomolar range with predominantly μ-opioid receptor selectivity. The positively charged NMe-enkephalins showed a higher antinociceptive activity (LinNMe: 298% and CycNMe: 205%), expressed as molar-dose normalized area under the curve (AUC) relative to morphine, than the neutral S-enkephalins (CycS: 122% and LinS: 130%).