Sustained Decrease in Cocaine-Maintained Responding in Rhesus Monkeys with 1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]- 4-(3-hydroxy-3-phenylpropyl)piperazinyl Decanoate, a Long-Acting Ester Derivative of GBR 12909

Sustained Decrease in Cocaine-Maintained Responding in Rhesus Monkeys with 1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]- 4-(3-hydroxy-3-phenylpropyl)piperazinyl Decanoate, a Long-Acting Ester Derivative of GBR 1290

Synthesis and Opioid Activity of Enantiomeric <i>N</i>-Substituted 2,3,4,4a,5,6,7,7a-Octahydro-1<i>H</i>-benzofuro[3,2-<i>e</i>]isoquinolines

A series of enantiomeric N-substituted 2,3,4,4a,5,6,7,7a-octahydro-1H-benzofuro[3,2-e]isoquinolines was synthesized. The (−)-enantiomers had much greater κ-, μ-, and δ-opioid receptor binding affinity than the corresponding (+)-enantiomers. Compounds (−)-1a, (−)-1b, and (−)-1c displayed subnanomolar binding affinity for the μ-receptor, and (−)-1b had a high affinity for the κ-receptor. Compound (−)-1a was a μ-partial agonist and κ-antagonist. Compound (−)-1b was a potent neutral μ-antagonist (Kd = 0.22 nM) and a κ-partial agonist

Design and Synthesis of 2- and 3-Substituted-3-phenylpropyl Analogs of 1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine and 1-[2-(Diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine: Role of Amino, Fluoro, Hydroxyl, Methoxyl, Methyl, Methylene, and Oxo Substituents on Affinity for the Dopamine and Serotonin Transporters

Novel derivatives of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909, 1) and 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (GBR 12935, 2) with various substituents in positions C2 and C3 of the phenylpropyl side chain were synthesized and evaluated for their ability to bind to the dopamine transporter (DAT) and the serotonin transporter (SERT). In the C2 series, the substituent in the S-configuration, with a lone-pair of electrons, significantly enhanced the affinity for DAT, whereas the steric effect of the substituent was detrimental to DAT binding affinity. In the C3 series, neither the lone electron pair nor the steric effect of the substituent seemed to affect DAT binding affinity, while sp2 hybridized substituents had a detrimental effect on affinity for DAT. In the series, the 2-fluoro-substituted (S)-10 had the highest DAT binding affinity and good DAT selectivity, while the 2-amino-substituted (R)-8 showed essentially the same affinity for DAT and SERT. The oxygenated 16 and 18 possessed the best selectivity for DAT

Discovery of the First N-Substituted 4β-Methyl-5-(3-hydroxyphenyl)morphan To Possess Highly Potent and Selective Opioid δ Receptor Antagonist Activity

A structurally novel opioid δ 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 Ke value of 0.15 nM in the [35S]GTPγS 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

Opioid Receptor Probes Derived from Cycloaddition of the Hallucinogen Natural Product Salvinorin A

As part of our continuing efforts toward more fully understanding the structure−activity relationships of the neoclerodane diterpene salvinorin A, we report the synthesis and biological characterization of unique cycloadducts through [4+2] Diels−Alder cycloaddition. Microwave-assisted methods were developed and successfully employed, aiding in functionalizing the chemically sensitive salvinorin A scaffold. This demonstrates the first reported results for both cycloaddition of the furan ring and functionalization via microwave-assisted methodology of the salvinorin A skeleton. The cycloadducts yielded herein introduce electron-withdrawing substituents and bulky aromatic groups into the C-12 position. Kappa opioid (KOP) receptor space was explored through aromatization of the bent oxanorbornadiene system possessed by the cycloadducts to a planar phenyl ring system. Although dimethyl- and diethylcarboxylate analogues 5 and 6 retain some affinity and selectivity for KOP receptors and are full agonists, their aromatized counterparts 13 and 14 have reduced affinity for KOP receptors. The methods developed herein signify a novel approach toward rapidly probing the structure−activity relationships of furan-containing natural products

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

Probes for Narcotic Receptor Mediated Phenomena. 39. Enantiomeric N-Substituted Benzofuro[2,3-<i>c</i>]pyridin-6-ols: Synthesis and Topological Relationship to Oxide-Bridged Phenylmorphans

Enantiomers of N-substituted benzofuro[2,3-c]pyridin-6-ols have been synthesized, and the subnanomolar affinity and potent agonist activity of the known racemic N-phenethyl substituted benzofuro[2,3-c]pyridin-6-ol can now be ascribed to the 4aS,9aR enantiomer. The energy-minimized structures suggest that the active enantiomer bears a greater three-dimensional resemblance to morphine than to an ostensibly structurally similar oxide-bridged phenylmorphan. Structural features of the conformers of N-substituted benzofuro[2,3-c]pyridin-6-ols were compared to provide the rationale for their binding affinity

Synthesis and Biological Evaluation of Tropane-like 1-{2-[Bis(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine (GBR 12909) Analogues

We have prepared azabicyclo[3.2.1] derivatives (C-3-substituted tropanes) that bind with high affinity to the dopamine transporter and inhibit dopamine reuptake. Within the series, 3-{2-[bis-(4-fluorophenyl)methoxy]ethylidene}-8-methyl-8-azabicyclo[3.2.1]octane (8) was found to have the highest affinity and selectivity for the dopamine transporter. These azabicyclo[3.2.1] (bridged piperidine) series of compounds differ from the well-known benztropines by a 2-carbon spacer between C-3 and a diarylmethoxy moiety. Interestingly, these new compounds demonstrated a much lower affinity for the muscarinic-1 site, at least a 100-fold decrease compared to benztropine. Replacing N-methyl with N-phenylpropyl in two of the compounds resulted in a 3−10-fold increase in binding affinity for the dopamine transporter. However, those compounds lost selectivity for the dopamine transporter over the serotonin transporter. Replacement of the ether oxygen in the diarylmethoxy moiety with a nitrogen atom gave relatively inactive amines, indicating the important role which is played by the ether oxygen in transporter binding. Reduction of the C-3 double bond in 8 gave 3α-substituted tropanes, as shown by X-ray crystallographic analyses of 11, 12, and 19. The 3α-substituted tropanes had lower affinity and less selectivity than the comparable unsaturated ligands

Probes for Narcotic Receptor Mediated Phenomena. 41. Unusual Inverse μ-Agonists and Potent μ-Opioid Antagonists by Modification of the N-Substituent in Enantiomeric 5-(3-Hydroxyphenyl)morphans

Conformational restraint in the N-substituent of enantiomeric 5-(3-hydroxyphenyl)morphans was conferred by the addition of a cyclopropane ring or a double bond. All of the possible enantiomers and isomers of the N-substituted compounds were synthesized. Opioid receptor binding assays indicated that some of them had about 20-fold higher μ-affinity than the compound with an N-phenylpropyl substituent (Ki = 2−450 nM for the examined compounds with various N-substituents). Most of the compounds acted unusually as inverse agonists in the [35S]GTP-γ-S functional binding assay using nondependent cells that stably express the cloned human μ-opioid receptor. Two of the N-substituted compounds with a cyclopropane ring were very potent μ-opioid antagonists ((+)-29, Ke = 0.17 and (−)-30, Ke =0.3) in the [35S]GTP-γ-S functional binding assay. By comparison of the geometry-optimized structures of the newly synthesized compounds, an attempt was made to rationalize their μ-opioid receptor affinity in terms of the spatial position of N-substituents

Neoclerodane Diterpenes as a Novel Scaffold for μ Opioid Receptor Ligands^†

Structural modification of salvinorin A, the active component of Salvia divinorum, has resulted in the synthesis of novel neoclerodane diterpenes with opioid receptor affinity and activity. We report in this study a nonnitrogenous neoclerodane diterpene with μ opioid receptor affinity (13) that is an agonist at μ opioid receptors. This represents the identification of a novel structural class of μ opioid receptor agonists