A structurally novel opioid κ receptor selective ligand has been identified. This compound, ...(3R)-7-hydroxy-N-((1S)-1-{(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinylmethyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic, 10) demonstrated high affinity for the κ receptor in the binding assay (κ K i = 0.3 nM) and highly potent and selective κ antagonism in the 35SGTP-γ-S assay using cloned opioid receptors (κ K i = 0.006 nM, μ/κ ratio = 570, δ/κ ratio > 16600).
(3R)-7-Hydroxy-N-((1S)-1-{(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinylmethyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic) was identified as a potent and selective κ ...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 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 35SGTPγS 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.
A series of novel benzimidazoles (BI) derived from the indole 2 was synthesized and evaluated as selective neuropeptide Y (NPY) Y1 receptor antagonists with the aim of developing antiobesity drugs. ...In our SAR approach, the (4-chlorophenoxy)methyl group at C-2 was kept constant and a series of BIs substituted with various piperidinylalkyl groups at N-1 was synthesized to identify the optimal spacing and orientation of the piperidine ring nitrogen relative to the benzimidazole. The 3-(3-piperidinyl)propyl in 33 was found to maximize affinity for the Y1 receptor. Because of the critical importance of Arg33 and Arg35 of NPY binding to the Y1 receptor, the incorporation of an additional aminoalkyl functionality to the structure of 33 was explored. Methyl substitution was used to probe where substitution on the aromatic ring was best tolerated. In this fashion, the C-4 was chosen for the substitution of the second aminoalkyl functionality. Synthesis of such compounds with a phenoxy tether using the 4-hydroxybenzimidazole 11 was pursued because of their relative ease of synthesis. Functionalization of the hydroxy group of 45 with a series of piperidinylalkyl groups provided the dibasic benzimidazoles 55−62. Among them, BI 56 demonstrated a K i of 0.0017 μM, which was 400-fold more potent than 33. To evaluate if there was a stereoselective effect on affinity for these BIs, the four constituent stereoisomers (69−72) of the BI 60 were prepared using the S- and R-isomers of bromide 17. Antagonist activity of these BIs was confirmed by measuring the ability of selected compounds to reverse NPY-induced forskolin-stimulated cyclic AMP. The high selectivity of several BI antagonists for the Y1 versus Y2, Y4, and Y5 receptors was also shown.
A series of benzimidazoles (
4) was synthesized and evaluated in vitro as potent and selective NPY Y1 receptor antagonists. Substitution of the piperidine nitrogen of
4 with appropriate R groups ...resulted in compounds with more than 80-fold higher affinity at the Y1 receptor compared to the parent compound
5 (R = 11). The most potent benzimidazole in this series was
21 (K
i = 0.052 nM).
A series of benzimidazoles (
4) was synthesized and evaluated in vitro as potent and selective NPY Y1 receptor antagonists. Substitution of the piperidine nitrogen of
4 with appropriate R groups resulted in compounds with more than 80-fold higher affinity at the Y1 receptor compared to the parent compound
5 (R H). The most potent benzimidazole in this series was
21 (K
i = 0.052 nM).
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 (EC50 = 22.6 nM).
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.
A structurally novel opioid δ receptor selective antagonist has been identified. This compound, ...(+)-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-2-azabicyclo3.3.1non-7-yl-(1-phenyl-1-cyclopentane)carboxamide (+)-KF4, (+)-4, showed a K e value of 0.15 nM in the 35SGTPγS functional assay. (+)-KF4 is also a δ inverse agonist with an IC50 value of 1.8 nM. To our knowledge, this is the first potent and selective δ opioid receptor antagonist from the 5-phenylmorphan class of opioids.
A three-component library of compounds was prepared in parallel using multiple simultaneous solution-phase synthetic methodology. The compounds were biased toward opioid receptor antagonist activity ...by incorporating (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (a potent, nonselective opioid pure antagonist) as one of the monomers. The other two monomers, which included N-substituted or unsubstituted Boc-protected amino acids and a range of substituted aryl carboxylic acids, were selected to add chemical diversity. Screening of these compounds in competitive binding experiments with the κ opioid receptor selective ligand 3HU69,593 led to the discovery of a novel κ opioid receptor selective ligand, N-{(2‘S)-3-(4-hydroxyphenyl)propanamido-3‘-methylbutyl}-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (8, RTI-5989-29). Additional structure−activity relationship studies suggested that 8 possesses lipophilic and hydrogen-bonding sites that are important to its opioid receptor potency and selectivity. These sites appear to exist predominantly within the κ receptor since the selectivity arises from a 530-fold loss of affinity of 8 for the μ receptor and an 18-fold increase in affinity for the κ receptor relative to the μ-selective ligand, (+)-N-trans-4-phenyl-2-butenyl-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (5a). The degree of selectivity observed in the radioligand binding experiments was not observed in the functional assay. According to its ability to inhibit agonist stimulated binding of 35SGTPγS at all three opioid receptors, compound 8 behaves as a μ/κ opioid receptor pure antagonist with negligible affinity for the δ receptor.
Structure-activity relationship studies were pursued within N-substituted-trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines in an effort to discover a peripherally selective opioid antagonist with ...high activity following systemic administration. Altering the size and the polarity of the N-substituent led to the discovery of 3 (LY246736). Compound 3 has high affinity for opioid receptors (Ki = 0.77, 40, and 4.4 nM for mu, kappa, and delta receptors, respectively). It is a potent mu receptor antagonist following parenteral and oral administration and distributes selectively (> 200-fold selectivity) to peripheral receptors. Thus, 3 has properties suitable for the clinical investigation of mu opioid receptor involvement in GI motility disorders.
A library of compounds biased toward opioid receptor antagonist activity was prepared by incorporating N-phenylpropyl-4β-methyl-5-(3-hydroxyphenyl)morphans as the core scaffold using simultaneous ...solution phase synthetic methodology. From this library, N-phenylpropyl-4β-methyl-5-(3-hydroxyphenyl)-7α-3-(1-piperidinyl)propanamidomorphan (−)-3b was identified as the first potent and selective κ opioid receptor antagonist from the 5-phenylmorphan class of opioids.
