Emetic activity of N-substituted norapomorphines

Area of Science:

• Pharmacology
• Medicinal Chemistry

Background:

• Norapomorphine is a known compound with pharmacological activity.
• N-substituted derivatives offer opportunities for modifying drug properties.

Purpose of the Study:

• To synthesize and evaluate N-substituted derivatives of norapomorphine.
• To assess the emetic and behavioral effects of these novel compounds.

Main Methods:

• Synthesis of norapomorphine and ten N-substituted derivatives.
• Emesis testing in dogs via intravenous, subcutaneous, and intramuscular administration.
• Modified Irwin mouse profile screen for behavioral effects and percutaneous absorption.

Main Results:

• N-ethyl and N-n-propyl norapomorphine derivatives demonstrated potent emetic activity in dogs at low doses (0.00025-0.0005 mg/kg).
• These derivatives also showed significant behavioral effects in mice, with minimum effective intravenous doses of 0.013 mg/kg (N-ethyl) and 0.0024 mg/kg (N-n-propyl).
• Percutaneous absorption was confirmed in mice, and all tested compounds induced the stereotyped apomorphine behavior syndrome with non-serious hypotensive effects.

Conclusions:

• N-substituted norapomorphine derivatives, particularly N-ethyl and N-n-propyl, exhibit significant emetic and behavioral potency.
• These findings suggest that N-substitution is a viable strategy for developing potent norapomorphine analogs.
• The observed percutaneous absorption indicates potential for topical or transdermal delivery of these compounds.