Discovery and pharmacological characterization of a selective delta opiate receptor antagonist (CP-646,777)

CP-646,777 (compound 2a) is identified as a potent and selective delta opioid receptor antagonist. The synthesis, pharmacological evaluation, disposition characteristics and pharmacokinetic properties of this compound are reported herein. An approach for reducing clearance as measured by human liver microsomes is demonstrated. The significance of p-glycoprotein efflux on CNS disposition and on the pharmacological action of CP-646,777 is also discussed.