Identification of (3R)-7-Hydroxy-N-(1S)-1-{[3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide as a Novel Potent and Selective Opioid κ Receptor Antagonist

摘要

(3R)-7-Hydroxy-N-(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic) was identified as a potent and selective κopioid receptor antagonist. Structure-activity relationship (SAR) studies on JDTic analogues revealed that the 3R, 4R stereochemistry of the 3,4-dimethyl-4-(3-hydroxy-phenyl)piperidine core structure, the 3R attachment of the 7-hydroxy-1,2,3,4-tetrahydroiso-quinoline group, and the 1S configuration of the 2-methylpropyl (isopropyl) group were all important to its κ potency and selectivity. The results suggest that, like other κ opioid antagonists such as nor-BNI and GNTI, JDTic requires a second basic amino group to express potent and selective κ antagonist activity in the [~(35)S]GTPγS functional assay. However, unlike previously reported κ antagonists, JDTic also requires a second phenol group in rigid proximity to this second basic amino group. The potent and selective κ antagonist properties of JDTic can be rationalized using the "message-address" concept wherein the (3R,4R)-3,4-dimethyl-4-(hydroxyphenyl)piperidinyl group represents the message, and the basic amino and phenol group in the N substituent constitutes the address. It is interesting to note the structural commonality (an amino and phenol groups) in both the message and address components of JDTic. The unique structural features of JDTic will make this compound highly useful in further characterization of the κ receptor.