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1.  Structure-activity relationships of substituted 1H-indole-2-carboxamides as CB1 receptor allosteric modulators 
Bioorganic & medicinal chemistry  2015;23(9):2195-2203.
A series of substituted 1H-indole-2-carboxamides structurally related to compounds Org27569 (1), Org29647 (2) and Org27759 (3) were synthesized and evaluated for CB1 allosteric modulating activity in calcium mobilization assays. Structure-activity relationship studies showed that the modulation potency of this series at the CB1 receptor was enhanced by the presence of a diethylamino group at the 4-position of the phenyl ring, a chloro or fluoro group at the C5 position and short alkyl groups at the C3 position on the indole ring. The most potent compound (45) had an IC50 value of 79 nM which is ~ 2.5 and 10 fold more potent than the parent compounds 3 and 1, respectively. These compounds appeared to be negative allosteric modulators at the CB1 receptor and dose-dependently reduced the Emax of agonist CP55,940. These analogs may provide the basis for further optimization and use of CB1 allosteric modulators.
Graphical Abstract
doi:10.1016/j.bmc.2015.02.058
PMCID: PMC4547606  PMID: 25797163
CB1 receptor; allosteric modulators; Org compounds; structure-activity relationship
2.  Effect of 1-Substitution on Tetrahydroisoquinolines as Selective Antagonists for the Orexin-1 Receptor 
ACS chemical neuroscience  2015;6(4):599-614.
Selective blockade of the Orexin-1 receptor has been suggested as a potential approach to drug addiction therapy because of its role in modulating the brain's reward system. We have recently reported a series of tetrahydroisoquinoline-based OX1 selective antagonists. Aimed at elucidating SAR requirements in other regions of the molecule and further enhancing OX1 potency and selectivity, we have designed and synthesized a series of analogs bearing a variety of substituents at the 1-position of the tetrahydroisoquinoline. The results show that an optimally substituted benzyl group is required for activity at the OX1 receptor. Several compounds with improved potency and/or selectivity have been identified. When combined with structural modifications that were previously found to improve selectivity, we have identified compound 73 (RTIOX-251) with an apparent dissociation constant (Ke) of 16.1 nM at the OX1 receptor and >620-fold selectivity over the OX2 receptor. In vivo, compound 73 was shown to block the development of locomotor sensitization to cocaine in rats.
doi:10.1021/cn500330v
PMCID: PMC4400266  PMID: 25643283
Orexin; antagonist; selective; tetrahydroisoquinoline
3.  Diarylureas as Allosteric Modulators of the Cannabinoid CB1 Receptor: Structure–Activity Relationship Studies on 1-(4-Chlorophenyl)-3-{3-[6-(pyrrolidin-1-yl)pyridin-2-yl]phenyl}urea (PSNCBAM-1) 
Journal of Medicinal Chemistry  2014;57(18):7758-7769.
The recent discovery of allosteric modulators of the CB1 receptor including PSNCBAM-1 (4) has generated significant interest in CB1 receptor allosteric modulation. Here in the first SAR study on 4, we have designed and synthesized a series of analogs focusing on modifications at two positions. Pharmacological evaluation in calcium mobilization and binding assays revealed the importance of alkyl substitution at the 2-aminopyridine moiety and electron deficient aromatic groups at the 4-chlorophenyl position for activity at the CB1 receptor, resulting in several analogs with comparable potency to 4. These compounds increased the specific binding of [3H]CP55,940, in agreement with previous reports. Importantly, 4 and two analogs dose-dependently reduced the Emax of the agonist curve in the CB1 calcium mobilization assays, confirming their negative allosteric modulator characteristics. Given the side effects associated with CB1 receptor orthosteric antagonists, negative allosteric modulators provide an alternative approach to modulate the pharmacologically important CB1 receptor.
doi:10.1021/jm501042u
PMCID: PMC4175001  PMID: 25162172
4.  Truncated Orexin Peptides: Structure–Activity Relationship Studies 
ACS Medicinal Chemistry Letters  2013;4(12):1224-1227.
Orexin receptors are involved in many processes including energy homeostasis, wake/sleep cycle, metabolism, and reward. Development of potent and selective ligands is an essential step for defining the mechanism(s) underlying such critical processes. The goal of this study was to further investigate the structure–activity relationships of these peptides and to identify the truncated form of the orexin peptides active at OX1. Truncation studies have led to OXA (17–33) as the shortest active peptide known to date with a 23-fold selectivity for OX1 over OX2. Alanine, d-amino acid, and proline scans have highlighted the particular importance of Tyr17, Leu20, Asn25, and His26 for agonist properties of OXA(17–33). The conformation of the C-terminus might also be a defining factor in agonist activity and selectivity of the orexin peptides for the OX1 receptor.
doi:10.1021/ml400333a
PMCID: PMC3975045  PMID: 24707347
Orexin; peptide; structure−activity relationship
5.  Truncated Orexin Peptides: Structure-Activity Relationship Studies 
ACS medicinal chemistry letters  2013;4(12):1224-1227.
Orexin receptors are involved in many processes including energy homeostasis, wake/sleep cycle, metabolism and reward. Development of potent and selective ligands is an essential step for defining the mechanism(s) underlying such critical processes. The goal of this study was to further investigate the structure-activity relationships of these peptides and to identify truncated form of the orexin peptides active at OX1. Truncation studies have led to OXA (17-33) as the shortest active peptide known to date with a 23-fold selectivity for OX1 over OX2. Alanine, D-amino acid and proline scans have highlighted the particular importance of Tyr17, Leu20, Asn25 and His26 for agonist properties of OXA(17-33). The conformation of the C-terminus might also be a defining factor in agonist activity and selectivity of the orexin peptides for the OX1 receptor.
doi:10.1021/ml400333a
PMCID: PMC3975045  PMID: 24707347
Orexin; Peptide; Structure-activity relationship
6.  Substituted Tetrahydroisoquinolines as Selective Antagonists for the Orexin 1 Receptor 
Journal of medicinal chemistry  2013;56(17):10.1021/jm400720h.
Increasing evidence implicates the orexin 1 (OX1) receptor in reward processes, suggesting OX1 antagonism could be therapeutic in drug addiction. In a program to develop an OX1 selective antagonist, we designed and synthesized a series of substituted tetrahydroisoquinolines and determined their potency in OX1 and OX2 calcium mobilization assays. Structure-activity relationship (SAR) studies revealed limited steric tolerance and preference for electron deficiency at the 7-position. Pyridylmethyl groups were shown to be optimal for activity at the acetamide position. Computational studies resulted in a pharmacophore model and confirmed the SAR results. Compound 72 significantly attenuated the development of place preference for cocaine in rats.
doi:10.1021/jm400720h
PMCID: PMC3849818  PMID: 23941044
Orexin; antagonist; selective; tetrahydroisoquinoline
7.  Deconstruction of the α4β2 Nicotinic Acetylchloine (nACh) Receptor Positive Allosteric Modulator des-Formylflustrabromine (dFBr) 
Journal of medicinal chemistry  2011;54(20):7259-7267.
des -Formylflustrabromine (dFBr; 1), perhaps the first selective positive allosteric modulator of α4β2 neuronal nicotinic acetylcholine (nACh) receptors, was deconstructed to determine which structural features contribute to its actions on receptors expressed in Xenopus ooycytes using 2-electrode voltage clamp techniques. Although the intact structure of 1 was found optimal, several deconstructed analogs retained activity. Neither the 6-bromo substituent nor the entire 2-position chain is required for activity. In particular, reduction of the olefinic side chain of 1, as seen with 6, not only resulted in retention of activity/potency but in enhanced selectivity for α4β2 versus α7 nACh receptors. Pharmacophoric features for the allosteric modulation of α4β2 nACh receptors by 1 were identified.
doi:10.1021/jm200834x
PMCID: PMC3200116  PMID: 21905680
8.  Effect of N-1/C-8 Ring Fusion and C-7 Ring Structure on Fluoroquinolone Lethality▿  
Antimicrobial Agents and Chemotherapy  2010;54(12):5214-5221.
Quinolones rapidly kill bacteria by two mechanisms, one that requires protein synthesis and one that does not. The latter, which is measured as lethal action in the presence of the protein synthesis inhibitor chloramphenicol, is enhanced by N-1 cyclopropyl and C-8 methoxy substituents, as seen with the highly lethal compound PD161144. In some compounds, such as levofloxacin, the N-1 and C-8 substituents are fused. To assess the effect of ring fusion on killing, structural derivatives of levofloxacin and PD161144 differing at C-7 were synthesized and examined with Escherichia coli. A fused-ring derivative of PD161144 exhibited a striking absence of lethal activity in the presence of chloramphenicol. In general, ring fusion had little effect on lethal activity when protein synthesis was allowed, but fusion reduced lethal activity in the absence of protein synthesis to extents that depended on the C-7 ring structure. Additional fused-ring fluoroquinolones, pazufloxacin, marbofloxacin, and rufloxacin, also exhibited reduced activity in the presence of chloramphenicol. Energy minimization modeling revealed that steric interactions of the trans-oriented N-1 cyclopropyl and C-8 methoxy moieties skew the quinolone core, rigidly orient these groups perpendicular to core rings, and restrict the rotational freedom of C-7 rings. These features were not observed with fused-ring derivatives. Remarkably, structural effects on quinolone lethality were not explained by the recently described X-ray crystal structures of fluoroquinolone-topoisomerase IV-DNA complexes, suggesting the existence of an additional drug-binding state.
doi:10.1128/AAC.01054-10
PMCID: PMC2981251  PMID: 20855738
9.  Efficient Synthesis of the 2-amino-6-chloro-4-cyclopropyl-7-fluoro-5-methoxy-pyrido[1,2-c]pyrimidine-1,3-dione core ring system 
Tetrahedron letters  2009;50(7):785-789.
An optimized total synthesis of the 2-amino-6-chloro-4-cyclopropyl-7-fluoro-5-methoxy-pyrido[1,2-c]pyrimidine-1,3-dione core structure of a new fluoroquinolone-like class of antibacterial agents is described. This synthesis is highlighted by a nearly quantitative ring-closing reaction to form the pyrido[1,2-c]pyrimidine core. This bicyclic ring system serves as a scaffold for a family of biologically active compounds.
doi:10.1016/j.tetlet.2008.11.121
PMCID: PMC2631556  PMID: 20160840
10.  Use of Gyrase Resistance Mutants To Guide Selection of 8-Methoxy-Quinazoline-2,4-Diones▿  
Antimicrobial Agents and Chemotherapy  2008;52(11):3915-3921.
A series of 1-cyclopropyl-8-methoxy-quinazoline-2,4-diones was synthesized and evaluated for lowering the ratio of the antimicrobial MIC in gyrase resistance mutants to that in the gyr+ (wild type) using isogenic strains of Escherichia coli. Dione features that lowered this ratio were a 3-amino group and C-7 ring structure (3-aminomethyl pyrrolidinyl < 3-aminopyrrolidinyl < diazobicyclo < 2-ethyl piperazinyl). The wild-type MIC was also lowered. With the most active derivative tested, many gyrA resistance mutant types were as susceptible as, or more susceptible than, wild-type cells. The most active 2,4-dione derivatives were also more active with two quinolone-resistant gyrB mutants than with wild-type cells. With respect to lethality, the most bacteriostatic 2,4-dione killed E. coli at a rate that was affected little by a gyrA resistance mutation, and it exhibited a rate of killing similar to its cognate fluoroquinolone at 10× the MIC. Population analysis with wild-type E. coli applied to agar showed that the mutant selection window for the most active 2,4-dione was narrower than that for the cognate fluoroquinolone or for ciprofloxacin. These data illustrate a new approach to guide early-stage antimicrobial selection. Use of antimutant activity (i.e., ratio of the antimicrobial MIC in a mutant strain to the antimicrobial MIC in a wild-type strain) as a structure-function selection criterion can be combined with traditional efforts aimed at lowering antimicrobial MICs against wild-type organisms to more effectively afford lead molecules with activity against both wild-type and mutant cells.
doi:10.1128/AAC.00330-08
PMCID: PMC2573108  PMID: 18765690

Results 1-10 (10)