Structure activity studies related to 2-(3,4-dichlorophenyl)-N-methyl-N-[2-(1-pyrrolidinyl)-1-substituted-ethyl]acetamides: a novel series of potent and selective .kappa.-opioid agonists
Abstract:This paper describes the synthesis of a series of N-[2-(1-pyrrolidinyl)ethyl]acetamides 1, variously substituted at the carbon adjacent to the amide nitrogen (C1), and related analogues, together with their biological evaluation as opioid kappa agonists. In the first part of the study, the variants in N-acyl, N-alkyl, and amino functions were explored when the substituent at C1 was 1-methylethyl and the optimum was found to be exemplified by 2-(3,4-dichlorophenyl)-N-methyl-N-[(1S)-1-(1-methylethyl)-2- (1-pyrro… Show more
“…Conformational Space of κ -Agonists. Although the key structural features of U50,488 derivatives have been identified by SAR (Figure ), − the conformational preferences of the free ligand or that involved in the receptor−ligand complex have not been investigated in detail. , In addition, the dynamic nature of the structure is of additional interest since there are many freely rotatable bonds in each molecule. …”
Section: Resultsmentioning
confidence: 99%
“…Fortunately, some insights on the formation of 1 − 10 can be obtained from the structure−activity relationship (SAR) data for this ligand series. By varying the aryl ( 1 vs 2 ) , and amide ( 1 vs 9 , 10 ) − substituents, altering the chain length (spacer) between the aryl and amide group, modifying the cyclohexyl moiety ( 1 vs 3 − 8 ), − and changing the ring size that contains the tertiary nitrogen, SAR studies have identified various means of optimizing the receptor−ligand interaction to improve the κ-opioid receptor binding and selectivity. , Although a simple spirotetrahydrofuranyl substituent on the cyclohexane ring in U50,488 [ K i ( 1 ) = 0.9 nM] reveals an increased ligand binding [ K i ( 4 ) = 0.3 nM],15b dramatic effects in the μ/κ-selectivity are observed when the aryl group is modified in concert . Thus, CI-977 ( 5 ) displays greater selectivity (1575-fold) 7 for the κ-receptor as compared to 1 and 4 (280-fold) 15b.…”
The three-dimensional structure, dynamics, and binding modes of representative kappa-opioid agonists of the arylacetamide class (U50, 488; U69,593; U62,066; CI-977; ICI199,441; ICI197,067; BRL52,537; and BRL52,656) have been investigated using molecular modeling techniques. Systematic exploration of the conformational space of the ligand combined with molecular dynamics (MD) simulations in water revealed consistent conformational preferences for all the kappa-agonists in this series. The results were further compared with available X-ray and 1D- and 2D-NMR data to identify potential "lead" conformers for molecular docking. Ligand binding modes were initially determined using automated docking of two of the ligands (U50,488 and BRL52,537) to the kappa-opioid receptor. Extrapolation of the predicted binding mode to other members in this ligand series revealed similar docking preferences, with each ligand docked along the receptor helical axis. The binding modes were further refined using MD simulations of the receptor-ligand complexes. The results show a that salt bridge is formed between the amino proton of the ligands and the carboxylate group of Asp138 in TM3. This interaction most likely serves as a key anchoring point for the agonist association. Additional ligand contacts were noted with kappa-specific residues Ile294, Leu295, and Ala298, which may, in part, explain the kappa-selectivity in this series. In comparing the arylacetamides with opiate-based ligands, no evidence was found to link these classes through a common binding motif (except for the ion pair). The binding site model was also applied to explain the enantiomeric preference of U50,488 and to provide insight to the mu/kappa-selectivity of representative ligands in this series. Overall, the results provide a structure-based rationale for ligand recognition that is consistent both with site-directed mutagenesis experiments and structure-function relationship data.
“…Conformational Space of κ -Agonists. Although the key structural features of U50,488 derivatives have been identified by SAR (Figure ), − the conformational preferences of the free ligand or that involved in the receptor−ligand complex have not been investigated in detail. , In addition, the dynamic nature of the structure is of additional interest since there are many freely rotatable bonds in each molecule. …”
Section: Resultsmentioning
confidence: 99%
“…Fortunately, some insights on the formation of 1 − 10 can be obtained from the structure−activity relationship (SAR) data for this ligand series. By varying the aryl ( 1 vs 2 ) , and amide ( 1 vs 9 , 10 ) − substituents, altering the chain length (spacer) between the aryl and amide group, modifying the cyclohexyl moiety ( 1 vs 3 − 8 ), − and changing the ring size that contains the tertiary nitrogen, SAR studies have identified various means of optimizing the receptor−ligand interaction to improve the κ-opioid receptor binding and selectivity. , Although a simple spirotetrahydrofuranyl substituent on the cyclohexane ring in U50,488 [ K i ( 1 ) = 0.9 nM] reveals an increased ligand binding [ K i ( 4 ) = 0.3 nM],15b dramatic effects in the μ/κ-selectivity are observed when the aryl group is modified in concert . Thus, CI-977 ( 5 ) displays greater selectivity (1575-fold) 7 for the κ-receptor as compared to 1 and 4 (280-fold) 15b.…”
The three-dimensional structure, dynamics, and binding modes of representative kappa-opioid agonists of the arylacetamide class (U50, 488; U69,593; U62,066; CI-977; ICI199,441; ICI197,067; BRL52,537; and BRL52,656) have been investigated using molecular modeling techniques. Systematic exploration of the conformational space of the ligand combined with molecular dynamics (MD) simulations in water revealed consistent conformational preferences for all the kappa-agonists in this series. The results were further compared with available X-ray and 1D- and 2D-NMR data to identify potential "lead" conformers for molecular docking. Ligand binding modes were initially determined using automated docking of two of the ligands (U50,488 and BRL52,537) to the kappa-opioid receptor. Extrapolation of the predicted binding mode to other members in this ligand series revealed similar docking preferences, with each ligand docked along the receptor helical axis. The binding modes were further refined using MD simulations of the receptor-ligand complexes. The results show a that salt bridge is formed between the amino proton of the ligands and the carboxylate group of Asp138 in TM3. This interaction most likely serves as a key anchoring point for the agonist association. Additional ligand contacts were noted with kappa-specific residues Ile294, Leu295, and Ala298, which may, in part, explain the kappa-selectivity in this series. In comparing the arylacetamides with opiate-based ligands, no evidence was found to link these classes through a common binding motif (except for the ion pair). The binding site model was also applied to explain the enantiomeric preference of U50,488 and to provide insight to the mu/kappa-selectivity of representative ligands in this series. Overall, the results provide a structure-based rationale for ligand recognition that is consistent both with site-directed mutagenesis experiments and structure-function relationship data.
“…The first example of these compounds is U50488 (84) that has 50-fold selectivity for k receptor over m receptor. 159 Other agonists belonging to this class are U69593 (85), 160 PD117302 (86), 161,162 CI977 (enadoline (87)), 163,164 GR-89696 (88), [165][166][167] piperidine analogues (89) of GR-89696, 168,169 and pyrrolidinyl ethylacetamide derivatives (90,91), 170 all of which show high affinity and selectivity for k receptor over m and d receptors. A morphinan derivative, TRK-820 (92), exhibits high potency and k selectivity over m and d receptors.…”
Section: K-selective Agonists and Antagonistsmentioning
Opioid analgesics provide outstanding benefits for relief of severe pain. The mechanisms of the analgesia accompanied with some side effects have been investigated by many scientists to shed light on the complex biological processes at the molecular level. New opioid drugs and therapies with more desirable properties can be developed on the bases of accurate insight of the opioid ligand-receptor interaction and clear knowledge of the pharmacological behavior of opioid receptors and the associated proteins. Toward this goal, recent advances in selective opioid receptor agonists and antagonists including opioid ligand-receptor interactions are summarized in this review article.
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