Importance of phenolic address groups in opioid kappa receptor selective antagonists.

In vitro characterization and comparison of JDTic, its dehydroxy analogue and nor-BNI, and its dehydroxy analogue demonstrates that the N-substituted 3,4-dimethyl-(3-hydroxyphenyl)piperidine-derived antagonist, JDTic, relies more heavily on its phenol address group for affinity and antagonist activity relative to the corresponding naltrexone derived antagonists, nor-BNI. The structural flexibility of the former class of compound relative to the latter is postulated to underlie the difference.

Discovery of the first N-substituted 4beta-methyl-5-(3-hydroxyphenyl)morphan to possess highly potent and selective opioid delta receptor antagonist activity.

A structurally novel opioid delta receptor selective antagonist has been identified. This compound, (+)-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl-(1-phenyl-1-cyclopentane)carboxamide [(+)-KF4, (+)-4], showed a K(e) value of 0.15 nM in the [(35)S]GTPgammaS functional assay. (+)-KF4 is also a delta inverse agonist with an IC(50) value of 1.8 nM. To our knowledge, this is the first potent and selective delta opioid receptor antagonist from the 5-phenylmorphan class of opioids.

Design and synthesis of a novel series of 1,2-disubstituted cyclopentanes as small, potent potentiators of 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA) receptors.

2-Amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA) potentiators are ligands that act as positive allosteric modulators at the AMPA receptors. We recently disclosed a novel series of 2-arylpropylsulfonamides that were potent potentiators of responses mediated through AMPA receptors. To further define the structural requirements for activity in this series, new ring-constrained analogues were prepared and a new stereocenter was introduced. The potentiating activity was highly dependent on the stereochemistry at the 2-position of the disubstituted cyclopentane and was independent of the relative stereochemistry at the 1-position. Compound (R,R)-10 represents a potent, novel potentiator of iGluR4 flip receptors (EC(50) = 22.6 nM).

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 kappa receptor antagonist.

(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 kappa opioid receptor antagonist. Structure-activity relationship (SAR) studies on JDTic analogues revealed that the 3R,4R stereochemistry of the 3,4-dimethyl-4-(3-hydroxyphenyl)piperidine core structure, the 3R attachment of the 7-hydroxy-1,2,3,4-tetrahydroisoquinoline group, and the 1S configuration of the 2-methylpropyl (isopropyl) group were all important to its kappa potency and selectivity. The results suggest that, like other kappa opioid antagonists such as nor-BNI and GNTI, JDTic requires a second basic amino group to express potent and selective kappa antagonist activity in the [(35)S]GTPgammaS functional assay. However, unlike previously reported kappa antagonists, JDTic also requires a second phenol group in rigid proximity to this second basic amino group. The potent and selective kappa 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 kappa receptor.

Discovery of an opioid kappa receptor selective pure antagonist from a library of N-substituted 4beta-methyl-5-(3-hydroxyphenyl)morphans.

A library of compounds biased toward opioid receptor antagonist activity was prepared by incorporating N-phenylpropyl-4beta-methyl-5-(3-hydroxyphenyl)morphans as the core scaffold using simultaneous solution phase synthetic methodology. From this library, N-phenylpropyl-4beta-methyl-5-(3-hydroxyphenyl)-7alpha-[3-(1-piperidinyl)propanamido]morphan [(-)-3b] was identified as the first potent and selective kappa opioid receptor antagonist from the 5-phenylmorphan class of opioids.