Rigid Analogues Research Articles

DAT/SERT selectivity of flexible GBR 12909 analogs modeled using 3D-QSAR methods

The dopamine reuptake inhibitor GBR 12909 (1-{2-[bis(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine, 1) and its analogs have been developed as tools to test the hypothesis that selective dopamine transporter (DAT) inhibitors will be useful therapeutics for cocaine addiction. This 3D-QSAR study focuses on the effect of substitutions in the phenylpropyl region of 1. CoMFA and CoMSIA techniques were used to determine a predictive and stable model for the DAT/serotonin transporter (SERT) selectivity (represented by p K i (DAT/SERT)) of a set of flexible analogs of 1, most of which have eight rotatable bonds. In the absence of a rigid analog to use as a 3D-QSAR template, six conformational families of analogs were constructed from six pairs of piperazine and piperidine template conformers identified by hierarchical clustering as representative molecular conformations. Three models stable to y-value scrambling were identified after a comprehensive CoMFA and CoMSIA survey with Region Focusing. Test set correlation validation led to an acceptable model, with q 2 = 0.508, standard error of prediction = 0.601, two components, r 2 = 0.685, standard error of estimate = 0.481, F value = 39, percent steric contribution = 65, and percent electrostatic contribution = 35. A CoMFA contour map identified areas of the molecule that affect p K i (DAT/SERT). This work outlines a protocol for deriving a stable and predictive model of the biological activity of a set of very flexible molecules.

Synthesis and Cytotoxic Evaluation of Combretafurans, Potential Scaffolds for Dual-Action Antitumoral Agents

We have synthesized rigid analogues of combretastatin bearing a furan ring in place of the olefinic bridge. These compounds are cytotoxic at nanomolar concentrations in neuroblastoma cells, display a similar structure-activity relationship compared to combretastatin A4, and inhibit tubulin polymerization. We also show that the furan ring can be further functionalized. Thus, it is possible that combretafurans could act as scaffolds for the development of dual-action antitumoral agents.

Discovery of potent and stable conformationally constrained analogues of the MCH R1 antagonist SB-568849

A strategy of systematically targeting more rigid analogues of the known MCH R1 receptor antagonist, SB-568849, serendipitously uncovered a binding mode accessible to N-aryl-phthalimide ligands. Optimisation to improve the stability of this compound class led to the discovery of novel N-aryl-quinazolinones, benzotriazinones and thienopyrimidinones as selective ligands with good affinity for human melanin-concentrating hormone receptor 1.

Weak Interactions in the Crystal Structures of Tetraacetylenes Derived from Pentaerythrityl Tetraphenyl Ether

Tetrakis(4-ethynylphenyl)methane (7) is known to crystallize as an interpenetrated diamondoid network held together in part by weak C⋮CH···C⋮C interactions that define characteristic cyclic quartets of ethynyl groups. To test the ability of this motif to direct the crystallization of more flexible molecules, we synthesized a series of tetraacetylenes derived from pentaerythrityl tetraphenyl ether, and we solved their structures by X-ray diffraction. Pentaerythrityl tetrakis(4-ethynylphenyl) ether (4) and the more rigid analogue 7 crystallize isostructurally, even though their cores are significantly different in size and flexibility. This observation shows that C⋮CH···C⋮C interactions may have value in engineering molecular crystals. However, widely different structures are obtained by crystallizing pentaerythrityl tetrakis(3-ethynylphenyl) ether (5) and pentaerythrityl tetrakis(4‘-ethynyl-1,1‘-biphenyl-4-yl) ether (6), despite their close similarity to tetraacetylene 4. The unpredictably varied behavior ...

Synthesis of protected derivatives and short peptides of antAib, a novel Cα-tetrasubstituted α-amino acid of the Ac5c type possessing a fused anthracene fluorophore

Abstract The Nα-Boc and Nα-Fmoc protected derivatives of 2-amino-2,3-dihydro-1H-cyclopenta[b]anthracene-2-carboxylic acid (antAib), a novel fluorescent, achiral, α-amino acid, rigid analogue of the known 9-antAla and 2-antAla residues, and belonging to the class of Ciα→Ciα cyclized, Cα,α-disubstituted glycines (strong β-turn and helix inducers in peptides), were synthesized in seven steps from 1,2,4-trimethylbenzene. The UV absorption and fluorescence properties of Boc–antAib–OEt and Boc–antAib–OH are also described. Solution syntheses of the short peptides Boc–antAib– l -Ala–OMe, Fmoc– l -Ala–antAib– l -Ala–OMe, as well as Boc–Aib–antAib– l -Ala–OMe and the side product 2,5-dioxopiperazine cyclo-[antAib– l -Ala], are presented as examples of the coupling ability at both C- and N-termini of the antAib residue.

Further potential of the GABA receptor in the treatment of insomnia

The benzodiazepine binding site on the GABA A receptor is the target for the majority of hypnotics, including the nonbenzodiazepine ‘Z drugs’ (zaleplon, zolpidem, zopiclone and eszopiclone). Concerns still exist over long-term benzodiazepine use, and efforts are, therefore, being made to search for new hypnotic agents and alternative receptor target sites, with novel mechanisms of action. Clinically useful compounds, including GABA mimetics and GABA-uptake inhibitors, have been found by developing structurally rigid analogs of GABA. The GABA-site agonist 4,5,6,7-tetra hydroisoxazolo[5,4-c]pyridin-3-ol (THIP) shows high potency for extrasynaptic GABA A receptor subtypes, which are not primary targets for classical benzodiazepines or the Z drugs. Hence, THIP targets a novel set of GABA A receptors. The antiepileptic drug, tiagabine, is a specific blocker of the GAT-1 GABA-transporter, increasing GABA levels following synaptic GABA release. It is proposed that this promotes extrasynaptic GABA A receptor activity. In contrast, two other GABA analogs, pregabalin and gabapentin, are not GABA mimetics but appear to act at calcium channels responsible for neurotransmitter release, rather than at the GABA receptors. All of these GABA analogs modify sleep behaviors and so are potentially effective hypnotic drugs that provide an alternative to the benzodiazepine binding site of the GABA A receptor.

Synthesis and Pharmacological Characterization of Nicotinic Acetylcholine Receptor Properties of (+)- and (−)-Pyrido-[3,4-b]homotropanes

(+/-)-Pyrido[3,4-b]homotropane [(+/-)-1] is a conformationally rigid analogue of nicotine (2) or nornicotine (3) that showed high affinity for nicotinic acetylcholine receptors. Even though the synthesis and potent activity of this highly interesting compound was originally reported in 1986 (Kanne, D. B.; Ashworth, D. J.; Cheng, M. T.; Mutter, L. C.; Abood, L. G. Synthesis of the first highly potent bridged nicotinoid. 9-Azabicylo[4.2.l]nona[2,3-c]pyridine (pyrido[3,4-b]homotropane). J. Am. Chem. Soc. 1986, 108, 7864-7865), the individual optical isomers have not been prepared and studied. In this study, we report the synthesis of (+)- and (-)-1 and show that (+)-1 has Ki = 1.29 nM at the alpha4beta2* nAChR and has over 260 times higher affinity than (-)-1. Single-crystal X-ray analysis of an intermediate used to prepare the isomers established the absolute stereochemistry as (1S,6S)-(+)-1 and (1R,6R)-(-)-1. Surprisingly, both isomers failed to produce antinociception in the mouse tail-flick and hot-plate assays, engender nicotine-like responding in rat drug discrimination, or alter current amplitude in alpha4beta2- and alpha3beta4-containing cells. However, (-)-1 antagonized nicotine-induced antinociception with an ED50 of 0.07 microg/kg in the tail-flick assay. The reason for this unusual pharmacology is unknown, but it is possible that (-)-1 is acting at a non-epibatidine-sensitive receptor subtype to antagonize nicotine's effects in the tail-flick assay.

Diastereoselective synthesis of β-aminocyclopentene sulfonic acid via hetero Diels–Alder reaction

A new cyclopentene GABA analogue was synthesized as a conformationally rigid analogue of the epilepsy drug vigabatrin. N-Sulfinyl dienophile Diels–Alder methodology, followed by alkaline hydrolysis of the corresponding dihydrothiazine oxide, oxidation and deprotection of the amino group gave cis-4-aminocyclopent-2-ene-1-sulfonic acid. The corresponding N, N-dimethylsulfinamide was also obtained.

Synthesis and appetite suppressant activity of 1-aryloxy-2-substituted aminomethyltetrahydronaphthalenes as conformationally rigid analogues of fluoxetine

Several 1-aryloxy-2-substituted aminomethyltetrahydronaphthalenes ( 7– 21) as conformationally rigid analogues of fluoxetine were synthesized and evaluated for their anorexigenic and antidepressant activities. For SAR studies the related acyclic analogues ( 22– 27) were also prepared. Out of the 21 synthesized compounds, 10 compounds ( 9, 10, 11, 15, 16, 18, 21, 22, 23 and 27) exhibited significant anorexigenic activity (at 75 μmol/kg). Interestingly, all the compounds ( 7– 20, 22– 26) were devoid of antidepressant effect, except for compounds 21 and 27 in which the antidepressant activity was retained. Compound 16 emerged as the most active compound of the series with better anorexigenic activity (97.92%) compared to fluoxetine (76.25%) and even with a clinically used drug sibutramine, thus providing a new structural lead for appetite suppressants.

Structural, Mutagenic, and Kinetic Analysis of the Binding of Substrates and Inhibitors of Human Phenylethanolamine N-Methyltransferase

The X-ray structure of human phenylethanolamine N-methyltransferase (hPNMT) complexed with its product, S-adenosyl-L-homocysteine (4), and the most potent inhibitor reported to date, SK&F 64139 (7), was used to identify the residues involved in inhibitor binding. Four of these residues, Val53, Lys57, Glu219 and Asp267, were replaced, in turn, with alanine. All variants had increased Km values for phenylethanolamine (10), but only D267A showed a noteworthy (20-fold) decrease in its kcat value. Both WT hPNMT and D267A had similar kcat values for a rigid analogue, anti-9-amino-6-(trifluoromethyl)benzonorbornene (12), suggesting that Asp267 plays an important role in positioning the substrate but does not participate directly in catalysis. The Ki values for the binding of inhibitors such as 7 to the E219A and D267A variants increased by 2-3 orders of magnitude. Further, the inhibitors were shown to bind up to 50-fold more tightly in the presence of S-adenosyl-L-methionine (3), suggesting that the binding of the latter brings about a conformational change in the enzyme.

Photocyclization of a conformationally constrained 2-vinylbiphenyl

The synthesis and photochemical behavior of a rigid analog of syn-2-vinylbiphenyl are reported. This analog undergoes quantitative conversion to a tetrahydrobenzanthracene derivative upon irradiation in fluid solution. Product formation is proposed to occur via photocyclization to yield an unstable intermediate followed by an intramolecular thermal hydrogen shift. The intermediate can be observed upon irradiation at low temperature either in a rigid glass or in liquid propane solution. The temperature dependence of its decay is indicative of a tunneling mechanism for the hydrogen shift process.

Flattening and analytic continuation of affinoid morphisms: remarks on a paper of Gardener and Schoutens

We give an example of an affinoid curve without analytic continuation. We use this to produce an example of an affinoid morphism that cannot be flattened by a finite sequence of local blow-ups. Thus the global rigid analogue of Hironaka's complex analytic flattening theorem given by T. Gardener and H. Schoutens, in Theorem 2.3 of ?Flattening and subanalytic sets in rigid analytic geometry?, Proc. London Math. Soc (3) 83 (2001) 681?707, is not true. Since this is a key step in the proof of the affinoid elimination theorem (loc. cit. Theorem 3.12), that proof contains a serious gap. We also give an example of an affinoid subset of the plane that is not the image under a proper rigid analytic map of a set that is globally semianalytic in the domain of that map. This clarifies the relationship among several natural categories of rigid subanalytic sets.

Developmental toxicity of domoic acid in zebrafish ( Danio rerio)

Domoic acid (DA) is a rigid analog of the excitatory amino acid glutamate. It is produced by the diatom genus Pseudo-nitzschia and is a potent neurotoxin in both adult and developing animals. We have used zebrafish ( Danio rerio) as a model to investigate and characterize the developmental toxicity of DA. Domoic acid was administered by microinjection to fertilized eggs at the 128- to 512-cell stages in concentrations ranging from 0.12 to 17 mg/kg (DA/egg weight). DA reduced hatching success by 40% at 0.4 mg/kg and by more than 50% at doses of 1.2 mg/kg and higher. Fifty percent of embryos treated with 1.2 mg/kg DA showed marked tonic–clonic type convulsions at 2 days post fertilization. Four days post fertilization (dpf), all embryos treated with 4.0 mg/kg DA and higher showed a complete absence of touch response reflexes. Commencing 5 dpf, rapid and constant pectoral fin movements were observed, a response which may be related to the hallmark effect in rodents of stereotypic scratching. These data indicate that zebrafish show symptoms of developmental DA toxicity as well as a similar sensitivity comparable to the effects of DA characterized in laboratory rodents.

Stereocontrolled synthesis of conformationally restricted enantiopure triols and dihydroxy acids based on the norbornane framework

The synthesis of chiral, rigid analogues of glycerol and cyclitols has been achieved by means of the stereocontrolled reduction of chiral bridgehead-substituted camphorquinones. This simple and easy procedure exclusively affords dihydroxy derivatives with a 2,3- cis- exo-configuration. The employment of different hydrides has also allowed the synthesis of enantiopure 2,3-dihydroxy carboxylic acids with high diastereoselectivity.

Photoinduced Bergman Cycloaromatization of Imidazole‐Fused Enediynes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Rigid analogs of DMPP as probes for the nicotinic receptors

Chemical manipulation of the nicotinic agonist DMPP, endowed with modest activity on the central receptors, definitely improved its affinity and pharmacokinetic properties. Although their pharmacophore is somehow different from that of classical nicotinic ligands, some DMPP derivatives show low nanomolar affinity for the central nicotinic receptors. Introduction of rigidity in the structure of DMPP and in that of its analogue 1-(3-pyridyl)piperazine, resulted in molecules with lower or null affinity for the central nicotinic receptors. This suggests that the frozen structures chosen either do not represent the bioactive conformation, or their volume is not compatible with the space available within the interaction site.

Photoinduced Bergman cycloaromatization of imidazole-fused enediynes

A series of 4,5-bis-(alkyn-1-yl)imidazoles—‘imidazole-fused’ enediynes—were synthesized and their reactivities in photoinduced Bergman cycloaromatization reactions were determined. The more conformationally rigid analogues gave cycloaromatized products in good yields upon irradiation (450 W low-pressure mercury lamp, ambient temperature). A bicyclic analogue ( 3 ) was shown to cleave supercoiled plasmid DNA.

Synthesis of Benzobicyclo[2.2.1]heptylimidazoles as Conformationally Constrained Adrenergic Receptor Antagonists

A facile method for the preparation of conformationally rigid analogues of the adrenergic α-2 receptor antagonist atipamezole and the adrenergic α-2 receptor agonist medetomidine has been developed. The efficient benzyne [4+2] cycloaddition reaction was used to give the core 7-acetylbenzonorbomadiene structure, which was subsequently elaborated to the corresponding imidazole-based syn and anti isomers by means of the classical Bredereck's method.

Synthesis and metal complexation properties of Ph-DTPA and Ph-TTHA: novel radionuclide chelating agents for use in nuclear medicine

We wish to report the synthesis and metal complexation properties of new radionuclide chelating agents for use in nuclear medicine. The strategy includes the facile preparation of rigid analogues of DTPA and TTHA possessing an aromatic ring. The aromatic structure used increased the stability of the complexes formed (pre-organization concept) and they are easily functionalised for attaching to any support. The poly(amino)poly(carboxylic) acids, Ph-DTPA (5a) and Ph-TTHA (5b) were obtained in five steps from phenylenediamine as the starting material with overall yields of 42 and 20%, respectively. The key step in this synthetic process is the preparation of tri- and tetra-amino compounds, 3a and 3b, respectively. In order to assess the ability of both ligands to complex with different metals ((111)In, (153)Sm, (90)Y, (177)Lu, (213)Bi, (225)Ac), along with their suitability for use in nuclear medicine, we used a number of complementary tests. We were able to demonstrate the high complexation capacity of Ph-DTPA (5a) with a broad range of radionuclides in a slightly acidic medium. In vitro stability studies show the high stability of Ph-DTPA with (111)In in human serum, a necessary condition for all medical applications. The protonation constant (log K(H)(i)) of Ph-DTPA (5a) was determined by potentiometric methods.

Acute phase gene expression in mice exposed to the marine neurotoxin domoic acid

Domoic acid is a rigid analog of the neurotransmitter glutamate and a potent agonist of kainate subtype glutamate receptors. Persistent activation of these receptor subtypes results in rapid excitotoxicity, calcium dependent cell death and neuronal lesions in areas of the brain where kainate pathways are concentrated. To better understand responses to domoic acid induced excitotoxicity, microarrays were used to profile gene expression in mouse brain following domoic acid exposure. Adult female mice were subjected intraperitoneally to domoic acid at the lethal dose 50, killed and dissected at 30, 60 and 240 min post-injection. Total brain RNA from treated mice was compared with time-matched controls on Agilent 22K feature microarrays. Real-time PCR was performed on selected genes. For the 30, 60 and 240 min time points, 3.96%, 3.94% and 4.36% of the genes interrogated were differentially expressed ( P-value≤0.01), respectively. Rigorous filtering of the data resulted in a set of 56 genes used for trending analysis and K-medians and agglomerative clustering. The earliest genes induced consisted primarily of early response gene families (Jun, Fos, Ier, Egr, growth arrest and DNA damage 45) and the inflammatory response element cyclooxygenase 2. Some later responding genes involved glucocorticoid responses (Gilz, Sgk), cold inducible proteins (Cirbp, Rbm3), Map kinases (Map3k6) and NF-κB inhibition. Real-time PCR in male mice from an additional study confirmed the expression of several of these genes across gender. The transcriptional profile induced by domoic acid shared similarity with expression profiles of brain ischemia and other excitotoxins, suggesting a common transcriptional response.