Syntheses of Non-Peptidic Delta Opioid Agonists and Their Structure Activity Relationships.

Nagase, Hiroshi; Wakita, Hisanori; Kawai, Koji; Endoh, Takashi; Matsuura, Hirotoshi; Tanaka, Chiko; Takezawa, Yuko

doi:10.1016/s0021-5198(19)49890-9

Cited by 17 publications

(5 citation statements)

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“…On the other hand, compound 15b possesses almost the same binding affinity as SL-3111, with 7-fold less selectivity. Such good binding may be consistent with the presence of methyl groups in several nonpeptide ligands reported for this receptor, including the BW-series of piperazine derivatives,19a but as we reported in detail previously for SL-3111 and its precursor analogues, SL-3111 has a different structure−activity relationship with the δ-opioid receptor than the BW-series of piperazines. The results reported here are consistent with these earlier results.…”

Section: Resultssupporting

confidence: 89%

Exploring the Structure−Activity Relationships of [1-(4-tert-Butyl-3‘-hydroxy)benzhydryl-4-benzylpiperazine] (SL-3111), A High-Affinity and Selective δ-Opioid Receptor Nonpeptide Agonist Ligand

et al. 1999

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SL-3111 [1-(4-tert-butyl-3'-hydroxy)benzhydryl-4-benzylpiperazine] is a de novo designed, high-affinity and selective nonpeptide peptidomimetic agonist of the delta-opioid receptor. In a previous report we had described the unique biological characteristics of this ligand and also a need for further structural evaluation.(6) To pursue this, we have introduced a completely different heterocyclic template (2 and 3), which, based on molecular modeling studies, may present the required structural features to properly orient the pharmacophore groups. We also have made more subtle changes to the original piperazine scaffold (5 and 11). The biological activities of these compounds revealed an important participation of the scaffold in the ligand-receptor interaction. To further explore functional diversity on the scaffold, we have maintained the original piperazine ring and introduced four different functionalities at position 2 of the heterocyclic ring (15a-d; a = CH(2)-O-CH(2)-Ph; b = Me; c = CH(2)Ph; d = CH(2)OH). The biological activities observed for these compounds showed a very interesting trend in terms of the steric effects of the groups introduced at this position. A decrease of almost 2000-fold in affinity and potency at the delta-receptor was observed for 15c compared with 15b. This difference may be explained if we postulate that the bioactive conformation of these peptidomimetics is close to the minimal energy conformations calculated in our study. On the basis of these findings we have realized the importance of this position to further explore and simplify the structure of future generations of peptidomimetic ligands.

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Section: Resultssupporting

confidence: 89%

Exploring the Structure−Activity Relationships of [1-(4-tert-Butyl-3‘-hydroxy)benzhydryl-4-benzylpiperazine] (SL-3111), A High-Affinity and Selective δ-Opioid Receptor Nonpeptide Agonist Ligand

et al. 1999

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“…This has provided the impetus for the development of selective nonpeptide δ opioid agonists. Two major advances in the area of δ - selective agonists were the discoveries of diarylpiperazine derivative (±)-BW373U86 ( 1 ) and morphinan derivative (−)-TAN-67 ( 3 ) (Figure ) . Both compounds exhibit a high affinity for the δ opioid receptor with moderate selectivity with respect to the μ opioid receptor.…”

Section: Introductionmentioning

confidence: 99%

“…Two major advances in the area of δ-selective agonists were the discoveries of diarylpiperazine derivative (()-BW373U86 (1) 11 and morphinan derivative (-)-TAN-67 (3) (Figure 1). 12 Both compounds exhibit a high affinity for the δ opioid receptor with moderate selectivity with respect to the µ opioid receptor. An analogue of (+)-BW373U86, SNC-80 (2), 13 demonstrated an improved selectivity while retaining potent δ receptor agonist activity.…”

Section: Introductionmentioning

confidence: 99%

N,N-Diethyl-4-(phenylpiperidin-4-ylidenemethyl)benzamide: A Novel, Exceptionally Selective, Potent δ Opioid Receptor Agonist with Oral Bioavailability and Its Analogues

et al. 2000

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The design, synthesis, and pharmacological evaluation of a novel class of delta opioid receptor agonists, N, N-diethyl-4-(phenylpiperidin-4-ylidenemethyl)benzamide (6a) and its analogues, are described. These compounds, formally derived from SNC-80 (2) by replacing the piperazine ring with a piperidine ring containing an exocyclic carbon carbon double bond, were found to bind with high affinity and exhibit excellent selectivity for the delta opioid receptor as full agonists. 6a, the simplest structure in the class, exhibited an IC(50) = 0.87 nM for the delta opioid receptors and extremely high selectivity over the mu receptors (mu/delta = 4370) and the kappa receptors (kappa/delta = 8590). Rat liver microsome studies on a selected number of compounds show these olefinic piperidine compounds (6) to be considerably more stable than SNC-80. This novel series of compounds appear to interact with delta opioid receptors in a similar way to SNC-80 since they demonstrate similar SAR. Two general approaches have been established for the synthesis of these compounds, based on dehydration of benzhydryl alcohols (7) and Suzuki coupling reactions of vinyl bromide (8), and are herewith reported.

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“…Following this rationale the first nonpeptidic δ opioid antagonist, naltrindole (NTI) (see Chart ), was synthesized 6 as well as the closely related N -methyl analogue, oxymorphindole (OMI), which has a partial δ agonist profile in vitro . Recently, a novel class of octahydroisoquinolines, formally derived from OMI fragmentation, including the δ antagonist (+)-3 (SB 205588) , and the δ agonists TAN67 and ( − )-6 (SB 213698), has been described. In addition, two piperazine derivatives, (±)-BW373U86 and one of its methoxy analogues SNC 80, which show clear structural differences compared to the previously known δ ligands, have been identified as potent and selective δ agonists.…”

mentioning

confidence: 99%

Discovery of a Novel Class of Substituted Pyrrolooctahydroisoquinolines as Potent and Selective δ Opioid Agonists, Based on an Extension of the Message−Address Concept

Dondio¹,

Ronzoni²,

Eggleston³

et al. 1997

J. Med. Chem.

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This paper describes the design and synthesis of compounds belonging to a novel class of substituted pyrrolooctahydroisoquinolines which are potent and selective delta opioid agonists. Molecular modeling studies performed on known, selective delta ligands such as (+)-3 and the potent delta agonists SNC 80 led to the identification of the carboxamido moiety of the latter as a putative nonaromatic delta address. Insertion of this moiety onto the octahydroisoquinoline opioid message resulted in (+/-)-5b, a potent and selective delta ligand. The active enantiomer, (-)-5b, displayed nanomolar affinity for the delta receptor (Ki = 0.9 nM) with good mu/delta and kappa/delta binding selectivity ratios (140 and 1480, respectively). In addition, (-)-5b behaved as a full delta agonist in the mouse vas deferens bioassay having an IC50 = 25 nM and being antagonised in the presence of 30 nM naltrindole (NTI). These studies, based on the message-address concept, indicated that the nonaromatic (N,N-diethylamino)carbonyl moiety is a viable alternative to the classical benzene ring as a delta opioid address. Preliminary in vivo studies showed that (+/-)-5b produced a dose-related antinociception in the mouse abdominal constriction test after intracerebroventricular administration (ED50 = 1.6 micrograms/mouse).

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Syntheses of Non-Peptidic Delta Opioid Agonists and Their Structure Activity Relationships.

Cited by 17 publications

References 0 publications

Exploring the Structure−Activity Relationships of [1-(4-tert-Butyl-3‘-hydroxy)benzhydryl-4-benzylpiperazine] (SL-3111), A High-Affinity and Selective δ-Opioid Receptor Nonpeptide Agonist Ligand

Exploring the Structure−Activity Relationships of [1-(4-tert-Butyl-3‘-hydroxy)benzhydryl-4-benzylpiperazine] (SL-3111), A High-Affinity and Selective δ-Opioid Receptor Nonpeptide Agonist Ligand

N,N-Diethyl-4-(phenylpiperidin-4-ylidenemethyl)benzamide: A Novel, Exceptionally Selective, Potent δ Opioid Receptor Agonist with Oral Bioavailability and Its Analogues

Discovery of a Novel Class of Substituted Pyrrolooctahydroisoquinolines as Potent and Selective δ Opioid Agonists, Based on an Extension of the Message−Address Concept

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