RT Journal Article SR Electronic T1 Blood-Brain Barrier Permeability of Novel [d-Arg2]Dermorphin (1-4) Analogs: Transport Property Is Related to the Slow Onset of Antinociceptive Activity in the Central Nervous System JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 177 OP 184 DO 10.1124/jpet.103.064006 VO 310 IS 1 A1 Yoshiharu Deguchi A1 Yu Naito A1 Sumio Ohtsuki A1 Yusaku Miyakawa A1 Kazuhiro Morimoto A1 Ken-ichi Hosoya A1 Shinobu Sakurada A1 Tetsuya Terasaki YR 2004 UL http://jpet.aspetjournals.org/content/310/1/177.abstract AB To clarify the pharmacological characteristics of Nα-amidino-Tyr-d-Arg-Phe-βAla-OH (ADAB) and Nα-amidino-Tyr-d-Arg-Phe-MeβAla-OH (ADAMB), μ1-opioid receptor-selective [d-Arg2]dermorphin tetrapeptide analogs, the plasma pharmacokinetics, and the in vivo blood-brain barrier (BBB) transport of these peptides were quantitatively evaluated. The mechanism responsible for the BBB transport of these peptides was also examined. The in vivo BBB permeation influx rates of 125I-ADAB and 125I-ADAMB after an i.v. bolus injection into mice were determined to be 0.0515 ± 0.0284 μl/(min · g of brain) and 0.0290 ± 0.0059 μl/(min · g of brain), respectively, both rates being slower than that of 125I-Tyr-d-Arg-Phe-βAla-OH (125I-TAPA), a [d-Arg2]dermorphin tetrapeptide analog. To elucidate the BBB transport mechanism of ADAB and ADAMB, a conditionally immortalized mouse brain capillary endothelial cell line (TM-BBB4) was used as an in vitro model of the BBB. The internalization of both 125I-ADAB and 125I-ADAMB into cells was concentration-dependent with half-saturation constant (Kd) values of 3.76 ± 0.83 and 5.68 ± 1.75 M, respectively. μ The acid-resistant binding of both ADAB and ADAMB was significantly inhibited by dansylcadaverine (an endocytosis inhibitor) and poly-l-lysine and protamine (polycations), but it was not inhibited by 2,4-dinitrophenol, or at 4°C. These results suggest that ADAB and ADAMB are transported through the BBB with slower permeation rates than that of TAPA, and this is likely to be a factor in the slow onset of their antinociceptive activity in the central nervous system. The mechanism of the BBB transport of these drugs is considered to be adsorptive-mediated endocytosis. The American Society for Pharmacology and Experimental Therapeutics