Paul David Gesellchen

Opioid antinociceptive effects of delta-receptor antagonists

The antinociceptive effects of delta opioid receptor antagonists (ICI 154129 and ICI 174864) have been studied using the mouse writhing assay. When administered intracerebroventricularly (ICV), ICI 154129 and ICI 174864 produced dose-related inhibition of writhing with respective ED50s of 97 micrograms/mouse and 1.4 micrograms/mouse. Inhibition of writhing by ICI 174864 (3 micrograms, ICV) was antagonized by subcutaneous (SC) naloxone doses of 0.1 mg/kg and greater. Pretreatment of mice with 80 mg/kg (SC) of beta-funaltrexamine (beta-FNA), an irreversible mu-receptor antagonist, 28 hr before ICV injection of ICI 174864 shifted the dose-effect curve for ICI 174864 to the right (ED50 of 7.3 micrograms/mouse). When administered SC, ICI 174864 inhibited writhing with an ED50 of 8.5 mg/kg. Maximal inhibition occurred 30 min after SC administration and decreased 50% by 2 hr. After beta-FNA pretreatment, doses of ICI 174864 as high as 80 mg/kg (SC) did not inhibit writhing. There was no antinociceptive effect of ICI 174864 in mice chronically maintained on morphine, i.e., chronic morphine produced cross-tolerance to the delta antagonist. These results show that delta-selective receptor antagonists produced antinociception which was related to the mu-receptor, but was probably not a result of direct agonist action.

Comparison of two penicillamine-containing enkephalins: mu, not delta activity produces analgesia

Two penicillamine-containing enkephalin analogs were compared for inhibition of mouse writhing after intracerebroventricular administration. The delta receptor-selective analog was less potent in inhibiting writhing than the non-selective analog. Inhibition of writhing produced by the delta-selective analog was antagonized by very low doses of naloxone, and produced additive analgesic effects with the delta receptor antagonist, ICI 174864. These results suggest that inhibition of writhing was produced by mu receptor agonist activity, and not delta receptor agonist activity.

Development of an orally active tripeptide arginal thrombin inhibitor.

The parenteral agent efegatran was chosen for clinical evaluation after extensive SAR studies and subsequent collaborations with the HIDR. It was studied extensively in Phase 1 and Phase 2 clinical trials to determine if it could provide superior benefits to heparin for cardiovascular patients with unstable angina or thrombolysis during acute myocardial infarction. Analysis of data from Phase 2 clinical trials demonstrated that efegatran exhibited equivalent efficacy to heparin. As a consequence further development with this parenteral agent was discontinued.