PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-12 (12)
 

Clipboard (0)
None
Journals
Year of Publication
Document Types
1.  Novel Adamantyl Cannabinoids as CB1 Receptor Probes 
Journal of medicinal chemistry  2013;56(10):3904-3921.
In previous studies compound 1 (AM411), a 3-(1-adamantyl) analog of the phytocannabinoid (−)-Δ8-tetrahydrocannabinol (Δ8-THC) was shown to have improved affinity and selectivity for the CB1 receptor. In this work, we further explored the role of the 1-adamantyl group at the C-3 position in a series of tricyclic cannabinoid analogs modified at the 9-northern aliphatic hydroxyl (NAH) position. Of these, 9-hydroxymethyl hexahydrocannabinol 11 (AM4054) exhibited high CB1 affinity and full agonist profile. In the cAMP assay, the 11-hydroxymethyl cannabinol analog 24 (AM4089) had a partial agonist profile, with high affinity and moderate selectivity for rCB1 over hCB2. In vivo results in rat models of hypothermia and analgesia were congruent with in vitro data. Our in vivo data indicates that 3-(1-adamantyl) substitution, within NAH cannabinergics, imparts improved pharmacological profiles when compared to the corresponding, traditionally used, 3-dimethylheptyl analogs and identifies 11 and 24 as a potential useful in vivo CB1 cannabinergic probes.
doi:10.1021/jm4000775
PMCID: PMC3706088  PMID: 23621789
2.  A Novel Series of Piperidin-4-yl-1,3-Dihydroindol-2-ones as Agonist and Antagonist Ligands at the Nociceptin Receptor 
Journal of medicinal chemistry  2004;47(12):10.1021/jm034249d.
A series of N-(4-piperidinyl)-2-indolinones were discovered as a new structural class of nociceptin receptor (NOP) ligands. Unlike other previously reported classes of NOP receptor ligands, modifications of the piperidine N substituents afforded both potent agonists and antagonists, with modest selectivities over other opioid receptors. The SAR revealed in this new series will provide important insights for the development of pharmacophores for agonist and antagonist actions at the NOP receptor.
doi:10.1021/jm034249d
PMCID: PMC3852901  PMID: 15163178
3.  Non-peptidic and Potent Small-Molecule Inhibitors of cIAP-1/2 and XIAP Proteins 
Journal of medicinal chemistry  2010;53(17):6361-6367.
A series of compounds were designed and synthesized as antagonists of cIAP-1/2 and XIAP based upon our previously identified lead compound SM-122 (1). The most potent of these (7) binds to XIAP, cIAP-1 and cIAP-2 proteins with Ki values of 36, <1 and <1.9 nM, respectively. Consistent with its potent binding affinities to IAPs, 7 effectively antagonizes XIAP in a cell-free caspase-9 functional assay, efficiently induces cIAP-1 degradation in cells at concentrations as low as 10 nM, and triggers activation of caspases and PARP cleavage in the MDA-MB-231 breast cancer cell line. Compound 7 potently inhibits cell growth in the MDA-MB-231 cancer cell line with an IC50 value of 200 nM and is 9 times more potent than compound 1.
doi:10.1021/jm100487z
PMCID: PMC2936695  PMID: 20684551
4.  Structure–Activity Relationships for a Novel Series of Dopamine D2-like Receptor Ligands Based on N-Substituted 3-Aryl-8-azabicyclo[3.2.1]octan-3-ol 
Journal of medicinal chemistry  2008;51(19):6095-6109.
Discovering dopamine D2-like receptor subtype-selective ligands has been a focus of significant investigation. The D2R-selective antagonist 3-[4-(4-chlorophenyl)-4-hydroxypiperidinyl]methylindole (1, L741,626; Ki(D2R/D3R) = 11.2:163 nM) has previously provided a lead template for chemical modification. Herein, analogues have been synthesized where the piperidine was replaced by a tropane ring that reversed the selectivity seen in the parent compound, in human hD2LR- or hD3R-transfected HEK 293 cells (31, Ki(D2R/D3R) = 33.4: 15.5 nM). Further exploration of both N-substituted and aryl ring-substituted analogues resulted in the discovery of several high affinity D2R/D3R ligands with 3-benzofurylmethyl-substituents (e.g., 45, Ki(D2R/D3R) = 1.7:0.34 nM) that induced high affinity not achieved in similarly N-substituted piperidine analogues and significantly (470-fold) improved D3R binding affinity compared to the parent ligand 1. X-ray crystallographic data revealed a distinctive spatial arrangement of pharmacophoric elements in the piperidinol vs tropine analogues, providing clues for the diversity in SAR at the D2 and D3 receptor subtypes.
doi:10.1021/jm800532x
PMCID: PMC3157365  PMID: 18774793
5.  Probes for Narcotic Receptor Mediated Phenomena. 39.1 Enantiomeric N-Substituted Benzofuro[2,3-c]pyridin-6-ols: Synthesis and Topological Relationship to Oxide-bridged Phenylmorphans2 
Journal of medicinal chemistry  2009;52(23):7570-7579.
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.
doi:10.1021/jm9004225
PMCID: PMC2788676  PMID: 19627147
Oxide-bridged 5-phenylmorphans; N-phenethyl-substituted para-d-isomer; conformers; nitrogen inversion; opioid receptor binding; functional assay
6.  Structure–Activity Relationships Comparing N-(6-Methylpyridin-yl)-Substituted Aryl Amides to 2-Methyl-6-(substituted-arylethynyl)pyridines or 2-Methyl-4-(substituted-arylethynyl)thiazoles as Novel Metabotropic Glutamate Receptor Subtype 5 Antagonists† 
Journal of medicinal chemistry  2009;52(11):3563-3575.
The metabotropic glutamate receptor subtype 5 (mGluR5) has been implicated in anxiety, depression, pain, mental retardation, and addiction. The potent and selective noncompetitive mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP, 1) has been a critically important tool used to further elucidate the role of mGluR5 in these CNS disorders. In an effort to provide novel and structurally diverse selective mGluR5 antagonists, we previously described a set of analogues with moderate activity wherein the alkyne bond was replaced with an amide group. In the present report, extended series of both amide and alkyne-based ligands were synthesized. MGluR5 binding and functional data were obtained that identified (1) several novel alkynes with comparable affinities to 1 at mGluR5 (e.g., 10 and 20–23), but (2) most structural variations to the amide template were not well tolerated, although a few potent amides were discovered (e.g., 55 and 56). Several of these novel analogues show drug-like physical properties (e.g., cLogP range) 2–5) that support their use for in vivo investigation into the role of mGluR5 in CNS disorders.
doi:10.1021/jm900172f
PMCID: PMC2894482  PMID: 19445453
7.  N-(4-(4-(2,3-Dichloro- or 2-methoxyphenyl)piperazin-1-yl)-butyl)-heterobiarylcarboxamides with Functionalized Linking Chains as High Affinity and Enantioselective D3 Receptor Antagonistsγ 
Journal of medicinal chemistry  2009;52(8):2559-2570.
In the present report, the D3 receptor pharmacophore is modified in the 2,3-diCl-and 2-OCH3-phenyl piperazine class of compounds with the goal to improve D3 receptor affinity and selectivity. This extension of structure-activity relationships (SAR) has resulted in the identification of the first enantioselective D3 antagonists (R- and S-22) to be reported, wherein enantioselectivity is more pronounced at D3 than at D2, and that a binding region on the second extracellular loop (E2) may play a role in both enantioselectivity and D3 receptor selectivity. Moreover, we have discovered some of the most D3-selective compounds reported to date that show high affinity (Ki =1 nM) for D3 and ∼400-fold selectivity over the D2 receptor subtype. Several of these analogues showed exquisite selectivity for D3 receptors over >60 other receptors further underscoring their value as in vivo research tools. These lead compounds also have appropriate physical characteristics for in vivo exploration and therefore will be useful in determining how intrinsic activity at D3 receptors tested in vitro is related to behaviors in animal models of addiction and other neuropsychiatric disorders.
doi:10.1021/jm900095y
PMCID: PMC2760932  PMID: 19331412
dopamine; D3 receptor; cocaine; drug abuse; addiction
8.  Probes for Narcotic Receptor Mediated Phenomena. 37.1 Synthesis and Opioid Binding Affinity of the Final Pair of Oxide-Bridged Phenylmorphans, the ortho- and para-b Isomers and Their N-Phenethyl Analogues, and the Synthesis of the N-Phenethyl Analogues of the ortho- and para-d Isomers 
Journal of medicinal chemistry  2008;51(24):7866-7881.
In the isomeric series of 12 racemic topologically rigid N-methyl analogues of oxide-bridged phenylmorphans, all but two of the racemates, the ortho- and para-b-oxide-bridged phenylmorphansa 20 and 12, have remained to be synthesized. The b-isomers were very difficult to synthesize because of the highly strained 5,6-trans-fused ring junction that had to be formed. Our successful strategy required functionalization of the position para (or ortho) to a fluorine atom on the aromatic ring using an electron-withdrawing nitro group to activate that fluorine. The racemic N-phenethyl analogues 24 and 16 were moderately potent κ-receptor antagonists in the [35S]GTPγS assay. We synthesized the N-phenethyl-substituted oxide-bridged phenylmorphans in the ortho- and para-d oxide-bridged phenylmorphana series (51 and 52) which had not been previously evaluated using contemporary receptor binding assays to see whether they also have higher affinity for opioid receptors than their N-methyl relatives 46 and 47.
doi:10.1021/jm800913d
PMCID: PMC2605521  PMID: 19053757
Oxide-bridged 5-phenylmorphans; N-methyl and N-phenethyl-substituted ortho- and para-b-isomers; N-methyl and N-phenethyl-substituted ortho- and para-d-isomers; opioid receptor binding; functional assay
9.  Conformationally Constrained Analogues of Diacylglycerol. 29. Cells Sort Diacylglycerol-Lactone Chemical Zip Codes to Produce Diverse and Selective Biological Activities 
Journal of medicinal chemistry  2008;51(17):5198-5220.
Diacylglycerol-lactone (DAG-lactone) libraries generated by a solid-phase approach using IRORI technology produced a variety of unique biological activities. Subtle differences in chemical diversity in two areas of the molecule, the combination of which generates what we have termed “chemical zip codes”, are able to transform a relatively small chemical space into a larger universe of biological activities, as membrane-containing organelles within the cell appear to be able to decode these “chemical zip codes”. It is postulated that after binding to protein kinase C (PKC) isozymes or other non-kinase target proteins that contain diacylglycerol responsive, membrane interacting domains (C1 domains), the resulting complexes are directed to diverse intracellular sites where different sets of substrates are accessed. Multiple cellular bioassays show that DAG-lactones, which bind in vitro to PKCα to varying degrees, expand their biological repertoire into a larger domain, eliciting distinct cellular responses.
doi:10.1021/jm8001907
PMCID: PMC2574997  PMID: 18698758
10.  Hydrolytic Reactivity Trends among Potential Prodrugs of the O2-Glycosylated Diazeniumdiolate Family. Targeting Nitric Oxide to Macrophages for Antileishmanial Activity 
Journal of medicinal chemistry  2008;51(13):3961-3970.
Glycosylated diazeniumdiolates of structure R2NN(O)=NO-R’ (R’ = a saccharide residue) are potential prodrugs of the nitric oxide (NO)-releasing but acid-sensitive R2NN(O)=NO− ion. Moreover, cleaving the acid-stable glycosides under alkaline conditions provides a convenient protecting group strategy for diazeniumdiolate ions. Here we report comparative hydrolysis rate data for five representative glycosylated diazeniumdiolates at pHs 14, 7.4, and 3.8 - 4.6 as background for further developing both the protecting group application and the ability to target NO pharmacologically to macrophages harboring intracellular pathogens. Confirming the potential in the latter application, adding R2NN(O)=NO-GlcNAc (where R2N = diethylamino or pyrrolidin-l-yl and GlcNAc = N-acetylglucosamin-l-yl) to cultures of infected mouse macrophages that were deficient in inducible NO synthase caused rapid death of the intracellular protozoan parasite Leishmania major with no host cell toxicity.
doi:10.1021/jm8000482
PMCID: PMC2574667  PMID: 18533711
11.  1-(4-Methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one (Pyrovalerone) analogs. A promising class of monoamine uptake inhibitors 
Journal of medicinal chemistry  2006;49(4):1420-1432.
Dopamine, serotonin and norepinephrine are essential for neurotransmission in the mammalian system. These three neurotransmitters have been the focus of considerable research since modulation of their production and their interaction at monoamine receptors has profound effects upon a multitude of pharmacological outcomes. Our interest has focused on neurotransmitter reuptake mechanisms in a search for medications for cocaine abuse. Herein we describe the synthesis and biological evaluation of an array of 2-aminopentanophenones. This array has yielded selective inhibitors of the dopamine and norepinephrine transporters with little effect upon serotonin trafficking. A subset of compounds had no significant affinity at 5HT1A, 5HT1B, 5HT1C, D1, D2, or D3 receptors. The lead compound, racemic 1-(4-methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one 4a, was resolved into its enantiomers and the S isomer was found to be the most biologically active enantiomer. Among the most potent of these DAT/NET selective compounds are the 1-(3,4-dichlorophenyl)- (4u) and the 1-naphthyl- (4t) 2-pyrrolidin-1-yl-pentan-1-one analogs.
doi:10.1021/jm050797a
PMCID: PMC2602954  PMID: 16480278
12.  Hydrolytic Reactivity Trends among Potential Prodrugs of the O2-Glycosylated Diazeniumdiolate Family. Targeting Nitric Oxide to Macrophages for Antileishmanial Activity 
Journal of Medicinal Chemistry  2008;51(13):3961-3970.
Glycosylated diazeniumdiolates of structure R2NN(O)=NO−R′ (R′ = a saccharide residue) are potential prodrugs of the nitric oxide (NO)-releasing but acid-sensitive R2NN(O)=NO− ion. Moreover, cleaving the acid-stable glycosides under alkaline conditions provides a convenient protecting group strategy for diazeniumdiolate ions. Here, we report comparative hydrolysis rate data for five representative glycosylated diazeniumdiolates at pH 14, 7.4, and 3.8−4.6 as background for further developing both the protecting group application and the ability to target NO pharmacologically to macrophages harboring intracellular pathogens. Confirming the potential in the latter application, adding R2NN(O)=NO−GlcNAc (where R2N = diethylamino or pyrrolidin-l-yl and GlcNAc = N-acetylglucosamin-l-yl) to cultures of infected mouse macrophages that were deficient in inducible NO synthase caused rapid death of the intracellular protozoan parasite Leishmania major with no host cell toxicity.
doi:10.1021/jm8000482
PMCID: PMC2574667  PMID: 18533711

Results 1-12 (12)