In vitro and in vivo characterization of opioid activities of C-terminal esterified endomorphin-2 analogs

Previously, we have synthesized a series of endomorphin-2 (EM-2) analogs by the substitution of C-terminal amide group. In the present study, to further our knowledge of the influence of C-terminal esterified modification on the pharmacological activities, we investigated the in vitro and in vivo opioid activities of C-terminal esterified EM-2 analogs 1–3. Our results showed that the ED₅₀ values on contractions of the longitudinal muscle of distal colon induced by analogs 1–3 were about 1.5-fold higher, 2- and 8-fold lower than EM-2, respectively. In addition, intravenous (i.v.) injections of analogs 1 and 2 dose-dependently decreased the system arterial pressure (SAP) and heart rate (HR) in anesthetized rats, but the degree of the hypotension and bradycardia was significantly smaller relative to the parent. Moreover, analog 3 was almost ineffective. Nevertheless, all these analogs produced potent antinociception in the tail-flick test after intracerebroventricular (i.c.v.) injection, and this antinociception was inhibited by naloxone, indicating an opioid mechanism. In summary, these results gave the evidence that the conversion of C-terminal amide to esterified modification may play an important role in the regulation of opioid affinities and pharmacological activities.