Distribution and analgesia of [³H][D-Pen²,D-Pen⁵]enkephalin and two halogenated analogs after intravenous administration

To improve pharmacological characteristics of the delta-selective, cyclic peptide [D-Pen²,D-Pen⁵]enkephalin (DPDPE), modification by halogenation at the Phe⁴ residue was undertaken. The present study was to determine the extent [³H]DPDPE, [³H][p-Cl-Phe⁴]DPDPE and [p-¹²⁵IPhe⁴]DPDPE crosses the blood-brain barrier, elicits analgesia and to characterize selective organ distribution and stability after i.v. administration. A significantly greater percentage of total [³H][p-Cl-Phe⁴]DPDPE reached the brain after 10, 20 and 40 min as compared to [³H]DPDPE and both peptides were significantly displaced by pretreatment with naloxone or naltrindole. The amount of [³H]DPDPE detected in the brain was greater than that of [p-¹²⁵IPhe⁴]DPDPE. Distribution results revealed large amounts of the administered peptides were sequestered rapidly in the gall bladder and secreted into the small intestine. Hot-plate antinociception tests 5 min after i.v. administration (30 and 60 mg/kg) revealed [p-Cl-Phe⁴]DPDPE to elicit a much greater analgesic effect as compared to DPDPE or [p-¹²⁵IPhe⁴]DPDPE. These results provide evidence that [p-Cl-Phe⁴]DPDPE has a greater apparent distribution to the brain and has a greater effect on the antinociception threshold as tested on the hot-plate than DPDPE or [p-¹²⁵IPhe⁴]DPDPE. Stability of unlabeled and tritiated DPDPE and [p-Cl-Phe⁴]DPDPE was determined both in vitro and in vivo; both unlabeled and tritiated DPDPE and [p-Cl-Phe⁴]DPDPE remain intact.