Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Imides”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 685 records · Page 38Linked to original sources
PubMed2003

Molecular mechanics and dynamics simulations of various dispersant models on the water surface (001).

Five dispersant-molecule models of succinimide, acrylate, imide, phenylsulfonic and salicyl were used to study their interactions with the water surface (001). The interaction energy, molecular configuration, charge distribution and radial distribution function (RDF) curve for each of the dispersant molecules were analyzed from the molecular mechanics (MM) and molecular dynamics (MD) simulation results. It can be seen that the system energies, mostly electrostatic and hydrogen bond energies, were reduced significantly when the dispersant molecules interacted with the water surface. The hydrophilic group of a dispersant molecule can attach itself to the water surface firmly and reach for a stable energy-minimized configuration, which is helpful to the dispersants' dispersancy. The influence exerted by the hydrophobic group of the dispersant molecule, which was the substituted hydrocarbon chain of n-octadecanyl in this paper, is discussed in comparison with the naked polar headgroup. Steric configuration, charge distribution and substitute hydrocarbon chain of the dispersant molecule influenced the interaction between dispersants and polar water surface.

Acrylates↗
PubMed1992

Structure-activity relationships among noncyclic dicarboxamide Li(+)-selective carriers studied in lipid bilayer membranes.

The structure-activity relationships among three noncyclic diimide ionophores, designed to be Li+ carriers, were studied in lipid bilayer membranes. These ionophores (ETH1644, ETH1810, and ETH1811) vary in their N-imide substituents, going from two isobutyls to one isobutyl and one cyclohexyl to two cyclohexyls, respectively. ETH1811 was found to form two types of complexes with 1:1 and 1:2 ion-carrier stoichiometries, the former type dominant over most of the ionophore (0.1-10 microM) and salt (0.01-1.0 M) concentration ranges studied. In contrast, ETH1644 and ETH1810 were previously found to form a single type of complex with the 1:2 stoichiometry. The alkali cations selectivity sequence induced by ETH1811 is Li+ (1) greater than Na+ (0.08) greater than K+ (0.02) greater than Cs+ (0.008). These ETH1811-induced ionic selectivites as well as its relative potency in ion transport were found to be inferior to those of ETH1644 and ETH1810 (the latter being the best in this series). The conductance-voltage relationships reported here, for all three ionophores transporting alkali cations, were found to fit with a transport mechanism in which the diffusion of the ion-ionophore complex across the membrane is the single rate-limiting step, with the following exceptions: The addition of the dissociation of the ion-carrier complex as a second rate limiting step, for the Li(+)-ETH1810 and the Li(+)-ETH1811 systems. For ETH1810 the kinetics of the dissociation step is a minor, whereas for ETH1811 case it is a significant, addition (the ratio of the diffusion to dissociation rate constants being 0.08 and 0.2, respectively). The implications of the effects of the continuous structural change of these ionophores on their performance as ion carriers and on the design and synthesis of improved Li(+)-selective ionophores are discussed.

Amides↗
PubMed1981

A study of Li+-selective permeation through lipid bilayer membranes mediated by a new ionophore (AS701).

The neutral, noncyclic, imide and ether containing ionophore AS701, has been developed as Li+-selective molecule, to be used potentially as an aid in the Li+-therapy of manic-depressive illness. The present report is a characterization of this molecule in neutral lipid bilayer membranes. This ionophore was found to render the bilayers Li+-selective, acting as a selective carrier of monovalent cations. In addition, this molecule was found to be capable of acting as a selective carrier of monovalent anions. For both types of ions, the rate-limiting step in the process of permeation was found to be the diffusion of the carrier-ion complex through the membrane. The membrane-permeating species were found to be 2 : 1 carrier-ion complexes, carrying either a monovalent cation or a monovalent anion. The selectivity sequence among the ions studied being: Li+(1) greater than ClO4-(0.7) greater than Na+(0.07) greater than K+(0.016) greater than Rb+(0.0095) greater than Cs+(0.0083) greater than Cl-(0.001). Mg2+ and SO42- were found to be impermeant (under present experimental conditions). This sequence shows that the AS701 molecule has low selectivity for ions present in biological media, among those studied (i.e. Na+, K+, Mg2+, Cl- and SO42-). This indicates that these ions will not interfere in the Li+ permeability induced by this carrier in vivo, and that the carrier will not interfere in the normal transport processes of these ions.

Anions↗
PubMed1984

Antiviral action of 5-amino-2-(2-dimethyl-aminoethyl)benzo-[de]-isoquinolin-1,3-dion e.

A newly synthesized imide derivative of 3-nitro-1,8-naphthalic acid, 5-amino-2-(2-dimethylaminoethyl)benzo-[de]-isoquinolin-1,3-dione (designated M-FA-142), was tested on chick embryo cells against herpes simplex virus type 1 (HSV-1) and vaccinia virus (VV), and on Vero cells against African swine fever virus (ASFV). At a concentration of 4 micrograms/ml the drug inhibited VV replication by about one order of magnitude, and that of HSV-1 by about three orders of magnitude. A minor effect was shown against ASFV. Virus inhibition was found to depend on the amount of drug and multiplicity of infection. No virucidal effect was observed on the viruses tested, except for a slight effect on HSV-1. Inhibition of virus growth could be reversed when the drug was removed from the cell culture medium. Serial passages of HSV-1 and VV in the presence of the drug caused the appearance of drug-resistant viruses.

Adenine↗
PubMed2005

Structure-intrinsic activity relationship studies in the group of 1-imido/amido substituted 4-(4-arylpiperazin-1-yl)cyclohexane derivatives; new, potent 5-HT1A receptor agents with anxiolytic- like activity.

Introduction of 1,4-disubstituted cyclohexane ring in the structure of flexible long chain arylpiperazines resulted in linearly constrained, potent serotonin (5-HT)(1A) ligands. In order to trace structure-intrinsic activity relationships in this group, a new series of 1-substituted 4-(4-arylpiperazin-1-yl)cyclohexane derivatives with different cyclic imide/amide termini, and their flexible, tetramethylene analogues were synthesized and pharmacologically evaluated for 5-HT(1A) receptors. In vitro binding experiments revealed that all the compounds were potent 5-HT(1A) receptor agents (K(i) = 1.9-74 nM). Some derivatives tested additionally showed also high affinity for alpha(1)-adrenergic receptors (K(i) = 2.9-101 nM) and for 5-HT(7) receptors. Functional in vivo examination revealed that rigid ligands with o-OCH(3) group in the aryl moiety and cyclic imide system in the opposite terminal behaved like postsynaptic 5-HT(1A) receptor antagonists. On the other hand, unsubstituted, m-Cl, or m-CF(3) substituted derivatives as well as those with cyclic amide group in the terminal fragment exhibited agonistic or partial agonistic activity. Three out of four derivatives tested, that is, postsynaptic 5-HT(1A) antagonists 9 and 10, and partial agonist 16, showed anxiolytic-like activity in the conflict drinking (Vogel) test in rats.

Adrenergic alpha-Agonists↗
PubMed2005

Syntheses, in vitro antibacterial and antifungal activities of a series of N-alkyl, 1,4-dithiines.

A series of dithiines were synthesized by cyclization of 4-(alkylamino)-4-oxobutanoic acids under the action of SOCl2. Their in vitro antibacterial and antifungal activities have been evaluated against reference strains and versus reference compounds. The so-called 'isoimides' 2a, 2b were totally inactive whereas some imides had low MICs for few bacteria and for few fungal microorganisms.

Anti-Bacterial Agents↗
PubMed2000

DNA sensing on a DNA probe-modified electrode using ferrocenylnaphthalene diimide as the electrochemically active ligand.

Naphthalene diimide derivative 1 carrying ferrocenyl moieties at the termini of imide substituents binds intact calf thymus DNA 4 times more strongly than the denatured DNA, and its complex with the intact DNA dissociates 80 times more slowly than that with the denatured DNA. On the basis of these observations, ligand 1 was applied to a probe of electrochemical DNA sensing. A thiol-linked single-stranded DNA probe was immobilized through the S-Au bonding to 20-30 pmol/mm2 on a gold electrode. Following hybridization with the complementary DNA, the electrode was soaked in a solution containing 1 (intercalation step) and then washed with buffer for 5 s. The cyclic voltammogram and differential pulse voltammogram for this electrode gave an electrochemical signal due to the redox reaction of 1 that was bound to the double-stranded DNA on the electrode. Thus, dA20 and the yeast choline transport gene were quantitated at the subpicomole level. The sensitivity of DNA detection was improved to 10 zmol by reducing the amount of immobilized DNA probe and protecting the uncovered surface of the electrode with 2-mercaptoethanol.

Base Sequence↗
PubMed1991

Kinetic and equilibrium analysis of a threading intercalation mode: DNA sequence and ion effects.

The interaction of a symmetric naphthalene diimide with alkylamino substituents at each imide position was investigated with the alternating sequence polymers, poly[d(A-T)]2 and poly[d(G-C)]2. Spectrophotometric binding studies indicate strong binding of the diimide to both sequences although the GC binding constant is 20-25 times larger than the AT binding constant. Analysis of the effects of salt concentration on the binding equilibria shows that the diimide forms two ion pairs in its complex with both polymers as expected for a simple dication. Stopped-flow kinetics experiments demonstrate that the diimide both associates and dissociates from DNA more slowly than classical intercalators with similar binding constants. Analysis of salt concentration effects on dissociation kinetics rate constants (kd) reveals that slopes in log kd versus log [Na+] plots are only approximately half the value obtained for classical dicationic intercalators that have both charged groups in the same groove. These kinetics results support a threading intercalation model, with one charged diimide substituent in each of the DNA grooves rather than with both side chains in the same groove, for the diimide complex with DNA. In the rate-determining step of the mechanism for dissociation of a threading complex only one ion pair is broken; the free side chain can then slide between base pairs to put both diimide side chains in the same groove, and this is followed by rapid full dissociation of the diimide. This sequential release of ion pairs makes the dissociation slope for dicationic threading intercalators more similar to the slope for classical monocationic intercalating ligands.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed2001

Difference in molecular structure of rod and cone visual pigments studied by Fourier transform infrared spectroscopy.

To investigate the local structure that causes the differences in molecular properties between rod and cone visual pigments, we have measured the difference infrared spectra between chicken green and its photoproduct at 77 K and compared them with those from bovine and chicken rhodopsins. In contrast to the similarity of the vibrational bands of the chromophore, those of the protein part were notably different between chicken green and the rhodopsins. Like the rhodopsins, chicken green has an aspartic acid at position 83 (D83) but exhibited no signals due to the protonated carboxyl of D83 in the C=O stretching region, suggesting that the molecular contact between D83 and G120 through water molecule evidenced in bovine rhodopsin is absent in chicken green. A pair of positive and negative bands due to the peptide backbone (amide I) was prominent in chicken green, while the rhodopsins exhibited only small bands in this region. Furthermore, chicken green exhibited characteristic paired bands around 1480 cm(-1), which were identified as the imide bands of P189 using site-directed mutagenesis. P189, situated in the putative second extracellular loop, is conserved in all the known cone visual pigments but not in rhodopsins. Thus, some region of the second extracellular loop including P189 is situated near the chromophore and changes its environment upon formation of the batho-intermediate. The results noted above indicate that differences in the protein parts between chicken green and the rhodopsins alter the changes seen in the protein upon photoisomerization of the chromophore. Some of these changes appear to be the pathway from the chromophore to cytoplasmic surface of the pigment and thus could affect the activation process of transducin.

Amino Acid Sequence↗
PubMed1978

Effect of pH on the cross-bridge arrangement in synthetic myosin filaments.

Synthetic thick filaments were cross-linked with dimethyl suberimidate at various pH values over the range pH 6.8---8.3. The rate of cross-linking myosin heads to the thick filament surface decreases significantly over a narrow pH range (7.4--8.0) despite the fact that the rate of the chemical reaction (amidination of lysine side chains) shows a positive pH dependence. The fall in rate cannot be ascribed to dissociation of the filament during the cross-linking reaction since the sedimentation boundary of the cross-linked filament (pH 8.3) remains unaltered in the presence of high salt (0.5 M). The decreased rate of cross-linking is also not caused by a shift in reactivity of a small number of highly reactive lysine groups, since the time course of cross-linking (pH 7.2) is unaffected by preincubation with a monofunctional imidate ester. Our results suggest that the heads of the myosin molecules move away from the thick filament surface at alkaline pH but are held close to the surface at neutral pH.

Dimethyl Suberimidate↗
PubMedDate not supplied

Vanadium complexes of the N(CH2CH2S)3(3-) and O(CH2CH2S)2(2-) ligands with coligands relevant to nitrogen fixation processes.

Vanadium(III) and vanadium(V) complexes derived from the tris(2-thiolatoethyl)amine ligand [(NS3)3-] and the bis(2-thiolatoethyl)ether ligand [(OS2)2-] have been synthesized with the aim of investigating the potential of these vanadium sites to bind dinitrogen and activate its reduction. Evidence is presented for the transient existence of (V(NS3)(N2)V(NS3), and a series of mononuclear complexes containing hydrazine, hydrazide, imide, ammine, organic cyanide, and isocyanide ligands has been prepared and the chemistry of these complexes investigated. [V(NS3)O] (1) reacts with an excess of N2H4 to give, probably via the intermediates (V(NS3)(NNH2) (2a) and (V(NS3)(N2)V(NS3) (3), the V(III) adduct [V(NS3)(N2H4)] (4). If 1 is treated with 0.5 mol of N2H4, 0.5 mol of N2 is evolved and green, insoluble [(V(NS3))n] (5) results. Compound 4 is converted by disproportionation to [V(NS3)(NH3)] (6), but 4 does not act as a catalyst for disproportionation of N2H4 nor does it act as a catalyst for its reduction by Zn/HOC6H3Pri2-2,6. Compound 1 reacts with NR1(2)NR2(2) (R1 = H or SiMe3; R2(2) = Me2, MePh, or HPh) to give the hydrazide complexes [V(NS3)(NNR2(2)] (R2(2) = Me2, 2b; R2(2) = MePh, 2c; R2(2) = HPh, 2d), which are not protonated by anhydrous HBr nor are they reduced by Zn/HOC6H3Pri2-2,6. Compound 2b can also be prepared by reaction of [V(NNMe2)(dipp)3] (dipp = OC6H3Pri2-2,6) with NS3H3. N2H4 is displaced quantitatively from 4 by anions to give the salts [NR3(4)][V(NS3)X] (X = Cl, R3 = Et, 7a; X = Cl, R3 = Ph, 7b; X = Br, R3 = Et, 7c; X = N3, R3 = Bu(n), 7d; X = N3, R3 = Et, 7e; X = CN, R3 = Et, 7f). Compound 6 loses NH3 thermally to give 5, which can also be prepared from [VCl3(THF)3] and NS3H3/LiBun. Displacement of NH3 from 6 by ligands L gives the adducts [V(NS3)(L)] (L = MeCN, nu CN 2264 cm-1, 8a; L = ButNC, nu NC 2173 cm-1, 8b; L = C6H11NC, nu NC 2173 cm-1, 8c). Reaction of 4 with N3SiMe3 gives [V(NS3)(NSiMe3)] (9), which is converted to [V(NS3)(NH)] (10) by hydrolysis and to [V(NS3)(NCPh3)] (11) by reaction with ClCPh3. Compound 10 is converted into 1 by [NMe4]OH and to [V(NS3)NLi(THF)2] (12) by LiNPri in THF. A further range of imido complexes [V(NS3)(NR4)] (R4 = C6H4Y-4 where Y = H (13a), OMe (13b), Me (13c), Cl (13d), Br (13e), NO2 (13f); R4 = C6H4Y-3, where Y = OMe (13g); Cl (13h); R4 = C6H3Y2-3,4, where Y = Me (13i); Cl (13j); R4 = C6H11 (13k)) has been prepared by reaction of 1 with R4NCO. The precursor complex [V(OS2)O(dipp)] (14) [OS2(2-) = O(CH2CH2S)2(2-)] has been prepared from [VO(OPri)3], Hdipp, and OS2H2. It reacts with NH2NMe2 to give [V(OS2)(NNMe2)(dipp)] (15) and with N3SiMe3 to give [V(OS2)(NSiMe3)(dipp)] (16). A second oxide precursor, formulated as [V(OS2)1.5O] (17), has also been obtained, and it reacts with SiMe3NHNMe2 to give [V(OS2)(NNMe2)(OSiMe3)] (18). The X-ray crystal structures of the complexes 2b, 2c, 4, 6, 7a, 8a, 9, 10, 13d, 14, 15, 16, and 18 have been determined, and the 51V NMR and other spectroscopic parameters of the complexes are discussed in terms of electronic effects.

Hydrazines↗
PubMed2002

Specific interactions of complementary mono- and multivalent guests with recognition-induced polymersomes.

We have explored the interactions of mono- and multivalent guests with Recognition-Induced Polymersomes (RIPs) formed from complementary random copolymers featuring diamidopyridine and thymine functionality. Addition of monovalent guests featuring imide functionality to these RIPs induced a temporary swelling of the vesicles, followed by dissociation of the vesicles due to competitive binding of the guest. Conversely, multivalent thymine-functionalized nanoparticle guests were rapidly incorporated into the RIPs, inducing a contraction of RIP diameter over time. These mono- and multivalent interactions were extremely specific: highly analogous control systems showed no interaction with the RIP structures. Taken together, these studies demonstrate highly selective molecular "lock and key" control over higher-order assembly and recognition processes.

Binding, Competitive↗
PubMed2003

Enantioselective synthesis of alpha,beta-disubstituted-beta-amino acids.

Highly diastereoselective and enantioselective addition of N-benzylhydroxylamine to imides 17 and 20-30 produces alpha,beta-trans-disubstituted N-benzylisoxazolidinones 19 and 31-41. These reactions proceed in 60-96% ee with 93-99% de's using 5 mol % of Mg(NTf2)2 and ligand 18. The product isoxazolidinones can be hydrogenolyzed directly to provide alpha,beta-disubstituted-beta-amino acids.

Amino Acids↗
PubMed2006

Energy transfer in calixarene-based cofacial-positioned perylene bisimide arrays.

The synthesis of multichromophoric perylene bisimide-calix[4]arene arrays with up to five perylene units (containing orange, violet, and green perylene bisimide chromophores) and of monochromophoric model compounds was achieved by subsequent imidization of mono-Boc functionalized calix[4]arene linkers with three different types of perylene bisimide dye units. The optical properties of all compounds were studied with UV/vis absorption and steady state and time-resolved fluorescence spectroscopy. Upon excitation of the inner orange dye at 490 nm of array 3, strong fluorescence emission of the outer green perylene bisimide (PBI) chromophore at 744 nm is observed. The fluorescence excitation spectra of compounds 3 and 4 (lambdadet = 850 nm) show all absorption bands of the parent chromophores (e.g., all perylene units contribute to the emission from S1 state of the green PBI). Thus, the fluorescence emission and excitation spectra as well as time-resolved data of fluorescence lifetimes in the absence (tauD = 5.1 ns) and in the presence of an acceptor (tauDA = 0.8 ns) suggest efficient energy transfer processes between the perylene bisimide dye units. For the bichromophoric array 4, the energy transfer rate is calculated to a value of 1.05 x 109 s-1. These results demonstrate highly efficient energy transfer in cofacially assembled dye arrays.

Biomimetic Materials↗
PubMed1984

A substituent constant analysis of the interaction of substituted naphthalene monoimides with DNA.

In a continuing analysis of substituent effects in intercalator-DNA interactions, an unsubstituted naphthalene monoimide, with a 3-(dimethylamino)propyl group on the imide nitrogen has been prepared along with 3- and 4-nitro- and 3- and 4-amino-substituted derivatives. These derivatives allow an evaluation of the importance of the Hammett substituent constant and of the substituent position on the binding of naphthalene monoimides to DNA. Viscosity and spectrophotometric analyses indicate that all five compounds bind to DNA by intercalation. The 4-nitro compound gives a smaller viscosity increase and binds only approximately one-third as strongly as the 3-nitro derivative. It is postulated that this difference is due to the significant angle that the 4-nitro group makes with the intercalated monoimide ring system. The 3-NO2 group can assume a coplanar configuration with the monoimide ring system, allowing more favorable interactions with DNA base pairs, larger viscosity increases, and stronger binding to DNA. The binding constants of the 3-substituted monoimides are in the order 2 greater than 4 greater than 1 and, thus, do not follow a substituent constant pattern. The Tm values from thermal melting of DNA, on the other hand, are in the order 2 greater than 1 greater than 4, suggesting that the enthalpy contributions are significantly different for the binding of the three compounds to DNA. van't Hoff plots support this finding and indicate that both enthalpy and entropy contribute significantly to the binding free energy of 1 and 2 while the binding of 4 is primarily an enthalpic process. Plots of Tm and 65 degrees C log K values as a function of substituent constant for 1, 2, and 4 are linear. CPK model building studies suggest that 4 can form a hydrogen bond with the 5' diester oxygen of the sugar-phosphate backbone of DNA in an intercalation complex. This would lead to more favorable energetics of binding but a loss of mobility and/or available binding configurations with a resulting enthalpy-entropy compensation in the binding free energy of 4. This series of compounds dramatically illustrates the steric and hydrogen bonding complexity that can arise in attempts to design drugs to favorably interact with a DNA intercalation site as a potential bioreceptor.

Animals↗
PubMed2003

Development of water-soluble prodrugs of the HIV-1 protease inhibitor KNI-727: importance of the conversion time for higher gastrointestinal absorption of prodrugs based on spontaneous chemical cleavage.

We designed and synthesized a series of water-soluble prodrugs of the HIV-1 protease inhibitor KNI-727 (1), which is a sparingly water-soluble drug with a water solubility of 5.5 microg/mL. These prodrugs, which contain a water-soluble auxiliary with two tandem-linked units, i.e., a self-cleavable spacer and a solubilizing moiety with an ionized amino function, exhibited a marked increase in water solubility (>10(4)-fold) compared with the parent drug 1. The mechanism of conversion to the parent drug 1 is not enzymatic but through a chemical cleavage at the spacer via an intramolecular cyclization-elimination reaction through an imide formation under physiological conditions. To diversify the conversion time for the parent drug regeneration, chemical modification of the auxiliary was carried out focusing on the introduction of cyclic tertiary amines, which can modify the basicity and/or conformational flexibility of the terminal amino function at the solubilizing moiety, and the change in bond length, which can attenuate the five-membered ring intermediate formation in the cleavage. These newly synthesized water-soluble prodrugs exhibited a practical water solubility with values greater than 50 mg/mL and enabled the constant regeneration of the parent drug 1 with diversified conversion times ranging from 4 min to 34 h as t(1/2) values under physiological conditions. All the water-soluble prodrugs tested regenerated the parent drug 1 in vivo as well as in vitro. A clear increase in the gastrointestinal absorption was observed in prodrugs 8, 12, and 13 with bioavailability (BA) values of 23%, 26%, and 29%, respectively. These BA values were 1.5-1.9-fold higher than that in the administration of the parent drug 1 alone. Other prodrugs showed only a similar or decreased BA compared to the parent drug 1. From these results, we found that not only a high water solubility but also an appropriate conversion time of the prodrug with a relatively narrow limit of around 35 min via intraduodenal administration was necessary for significant improvement of the gastrointestinal absorption in water-soluble prodrugs based on the spontaneous chemical cleavage. This is the first successful water-soluble prodrug that suggests an increased BA value greater than the parent drug in HIV-1 protease inhibitors and is the first study to show the importance of optimal conversion time in water-soluble prodrugs. Consequently, a water-soluble strategy that can control the conversion time would be extensively applicable to improve the gastrointestinal absorption of sparingly water-soluble drugs. The present information is an intriguing discovery and is one of the key factors that will contribute to the future design of practical water-soluble prodrugs.

Animals↗
PubMed2004

Synthesis, screening, and molecular modeling of new potent and selective antagonists at the alpha 1d adrenergic receptor.

In the present study, more than 75 compounds structurally related to BMY 7378 have been designed and synthesized. Structural variations of each part of the reference molecule have been introduced, obtaining highly selective ligands for the alpha(1d) adrenergic receptor. The molecular determinants for selectivity at this receptor are essentially held by the phenyl substituent in the phenylpiperazine moiety. The integration of an extensive SAR analysis with docking simulations using the rhodopsin-based models of the three alpha(1)-AR subtypes and of the 5-HT(1A) receptor provides significant insights into the characterization of the receptor binding sites as well as into the molecular determinants of ligand selectivity at the alpha(1d)-AR and the 5-HT(1A) receptors. The results of multiple copies simultaneous search (MCSS) on the substituted phenylpiperazines together with those of manual docking of compounds BMY 7378 and 69 into the putative binding sites of the alpha(1a)-AR, alpha(1b)-AR, alpha(1d)-AR, and the 5-HT(1A) receptors suggest that the phenylpiperazine moiety would dock into a site formed by amino acids in helices 3, 4, 5, 6 and extracellular loop 2 (E2), whereas the spirocyclic ring of the ligand docks into a site formed by amino acids of helices 1, 2, 3, and 7. This docking mode is consistent with the SAR data produced in this work. Furthermore, the binding site of the imide moiety does not allow for the simultaneous involvement of the two carbonyl oxygen atoms in H-bonding interactions, consistent with the SAR data, in particular with the results obtained with the lactam derivative 128. The results of docking simulations also suggest that the second and third extracellular loops may act as selectivity filters for the substituted phenylpiperazines. The most potent and selective compounds for alpha(1d) adrenergic receptor, i.e., 69 (Rec 26D/038) and 128 (Rec 26D/073), are characterized by the presence of the 2,5-dichlorophenylpiperazine moiety.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed2005

Cycloaddition chemistry of 2-vinyl-substituted indoles and related heteroaromatic systems.

[reaction: see text] The intramolecular Diels-Alder cycloaddition reaction (IMDAF) of several N-phenylsulfonylindolyl-substituted furanyl carbamates containing a tethered pi-bond on the indole ring were examined as an approach to the iboga alkaloid catharanthine. Only in the case where the tethered pi-bond contained two carbomethoxy groups did the [4 + 2]-cycloaddition occur. Push-pull dipoles generated from the Rh(II)-catalyzed reaction of diazo imides, on the other hand, undergo successful intramolecular 1,3-dipolar cycloaddition across both alkenyl and heteroaromatic pi-bonds to provide novel pentacyclic compounds in good yield and in a stereocontrolled fashion. The facility of the cycloaddition was found to be critically dependent on conformational factors in the transition state. Ligand substitution in the rhodium(II) catalyst markedly altered the product ratio between [3 + 2]-cycloaddition and intramolecular C-H insertion. The variation in reactivity reflects the difference in electrophilicity between the various rhodium carbenoid intermediates. Intramolecular C-H insertion is enhanced with the more electrophilic carbene generated using Rh(II) perfluorobutyrate.

Catalysis↗