Resolution of risperidone-induced hyperprolactinemia with substitution of quetiapine.

Objective: To report a case of risperidone-induced hyperprolactinemia that was successfully managed with quetiapine.

Case Summary: A 30-year-old white woman with schizoaffective disorder, depressive type, and comorbid alcohol and cocaine abuse was treated successfully for her psychotic symptoms with risperidone until she developed adverse effects consistent with hyperprolactinemia. This was confirmed by laboratory blood tests, as her prolactin level was 186.

Unusual cyclo-tetra and hexa peptidation of bis-boc-cystine with cystine-di-OMe: one step preparation of the novel 32- and 48-membered cyclotetracystine and cyclohexacystine.

The unprecedented formation of 32- and 48-membered macrocycles that inscribe 4 and 6 cystine units, in the peptidation of bis-Boc-cystine with cystine di-OMe is reported.

Studies on novel peptidomimetics having bi-directional dispositions of hydroxylated D-Pro-Gly motifs anchored on a C(2)-symmetric iminosugar-based foundation.

A rigid pyrrolidine based scaffold comprising of 2,5-dideoxy-2,5-imino-D-idaric acid (1) is developed. Attachment of peptide strands to the carboxylic groups at both ends of this novel template led to the peptidomimetics 2 and 3. Conformational analysis by NMR studies revealed that compounds 2b, 3b and 2c, 3c take interesting turn structures (C(2) symmetric for 2c and 3c) in DMSO-d(6) consisting of identical intramolecular hydrogen bonds at two ends between LeuNH --> sugar-OH as depicted in structure A, whereas 2a and 3a display structures with regular beta-turns with hydrogen bonds between LeuNH --> Boc-C=O in one-half of their molecular frameworks (structure B), characteristic of the turn structures commonly observed in "D-Pro-Gly"-containing peptides.

NMR study of cyclic peptides with renin inhibitor activity.

Several cyclic analogues of renin inhibitors, based on Glu-D-Phe-Lys motif have been investigated by NMR spectroscopy and molecular dynamics calculations (MD). The 15 membered macrocycle, resulting from Glu and Lys side-chain cyclization, exhibits conformational preference. The structural evidence from NMR shows the presence of hydrogen bond between Lys NH and Glu side-chain carbonyl, resulting in a 10 membered pseudo beta-turn-like structure.

Asymmetric synthesis of (+)-allo-quercitol and (+)-talo-quercitol via free radical cycloisomerization of an enantiomerically pure alkyne-tethered aldehyde derived from a carbohydrate.

We describe for the first time the free radical cyclization of enantiomerically pure alkyne-tethered aldehydes obtained from a carbohydrate (6, 7). The synthesis of compounds 6 and 7 obtained from a derivative of D-ribose is reported. These radical precursors have been submitted to cyclization with tributyltin hydride plus azobisisobutyronitrile to yield, after ring closure, two carbocycles, respectively.

Design, Synthesis, and Characterization of Tyrosinophanes, a Novel Family of Aromatic-Bridged Tyrosine-Based Cyclodepsipeptides.

A simple two-step design strategy has been developed for the synthesis of a large variety of a new class of tyrosine-based aromatic (Ph or Pyr) bridged cyclodepsipeptides (tyrosinophanes). The design is flexible with respect to the size of the ring and the nature of the bridging unit and permits the incorporation of a variety of amino acid residues inside or outside or both inside and outside the ring as illustrated here with the preparation of tyrosine-based macrocycles with aromatic (Ph or Pyr), cage-like alicyclic (adamantane) or simple polymethylene bridging units in ring sizes varying from 26-membered to 78-membered and containing leucine residues as part of the ring or as pendants on the exterior or both inside and outside the macrocyclic ring. (1)H NMR, FT-IR, and CD studies have indicated open-ring structures for these macrocycles.

Channel-forming, self-assembling, bishelical amphiphilic peptides: design, synthesis and crystal structure of Py(Aibn)2, n=2,3,4.

The design, synthesis, characterization and self-assembling properties of a new class of amphiphilic peptides, constructed from a bifunctional polar core attached to totally hydrophobic arms, are presented. The first series of this class, represented by the general structure Py(Aibn)2 (Py=2,6-pyridine dicarbonyl unit; Aib=alpha, alpha'-dimethyl glycine; n=1-4), is prepared in a single step by the condensation of commercially available 2,6-pyridine dicarbonyl dichloride with the methyl ester of homo oligoAib peptide (Aibn-OMe) in the presence of triethyl amine. 1H NMR VT and ROESY studies indicated the presence of a common structural feature of 2-fold symmetry and an NH.

2,5-Anhydro sugar diacid and 2,5-anhydro sugar diamine based symmetric peptidomimetics as potential HIV-1 protease inhibitors.

Conformationally constrained molecular frameworks of the 2,5-anhydro sugar diacid () and 2,5-anhydro sugar diamines (, ) were used to construct architecturally beautiful novel symmetric peptidomimetics -. Although none of these compounds showed any significant HIV-1 protease inhibitory activity, further refinements in design may lead to protease inhibitors based on these rigid carbohydrate-derived scaffolds.

Synthesis and conformational studies of peptidomimetics containing furanoid sugar amino acids and a sugar diacid.

Furanoid sugar amino acids (1) were synthesized and used as dipeptide isosteres to induce interesting turn structures in small linear peptides. They belong to a new variety of designed hybrid structures that carry both amino and carboxyl groups on rigid furanose sugar rings. Four such molecules, 6-amino-2,5-anhydro-6-deoxy-D-gluconic acid (3, Gaa) and its mannonic (4, Maa), idonic (5, Iaa), and a 3,4-dideoxyidonic (6, ddIaa) congeners were synthesized.

A study of prevalence and comorbidity of depression in alcohol dependence.

Depressive symptoms are wide spread in alcohol abusing patients of all ages and are much more common than diagnosable depressive disorder. Studies have reported that depression diagnosed in the current episode of alcoholism remits after two weeks of abstinence and detoxification from alcohol. Despite the high prevalence of depression in alcohol dependent individuals, the nature of the relationship between depressive disorder and alcohol abuse have been difficult to define.

Norbornene-constrained cyclic peptides with hairpin architecture: design, synthesis, conformation, and membrane ion transport.

A novel family of hairpin cyclic peptides has been designed on the basis of the use of norbornene units as the bridging ligands. The design is flexible with respect to the choice of an amino acid, the ring size, and the nature of the second bridging ligand as illustrated here with the preparation of a large number of norborneno cyclic peptides containing a variety of amino acids in ring sizes varying from 12- to 29-membered, with the choice of the second bridging ligand being a rigid norbornene (11, 13a,b), an adamantane unit (7a,b and 8), or a flexible cystine residue (4a,b and 10). The presence of built-in handles (as protected COOH groups) permits the attachment of a variety of subunits as shown here with the ligation of Leu-Leu, Val-Val, or Aib-Aib pendants in 4b, 7b, and 13b, respectively.

NMR study of the peptide present in the principal neutralizing determinant (PND) of HIV-1 envelope glycoprotein gp120.

The peptide sequence Gly-Pro-Gly-Arg-Ala-Phe (GPGRAF) is present in many principal neutralizing determinants (PND) of the human immunodeficiency virus type-1 (HIV-1). It has been shown that peptides from the PND sequence contain a significant beta turn in the conserved Gly-Pro-Gly-Arg sequence. In order to find out whether or not the smaller subunits also contain this turn, we have studied the NMR of a hexapeptide [GPGPRAF, peptide (I)], a heptapeptide Gly-Pro-Gly-Arg-Ala-Phe-Cys [GPGRAFC, peptide (II)] and a dodecapeptide [GPGRAFGPGRAF, peptide (III)], retaining the side chain protecting groups.

NMR study of dideoxynucleotides with anti-human immunodeficiency virus (HIV) activity.

The molecular structures of 3'-azido-2',3'-dideoxyribosylthymine 5'-triphosphate (AZTTP), 2',3'-dideoxyribosylinosine 5'-triphosphate (ddlTP), 3'-azido-2',3'-dideoxyribosylthymine 5'-monophosphate (AZTMP) and 2',3'-dideoxyribosyladenine 5'-monophosphate (ddAMP) have been studied by NMR to understand their anti-HIV activity. For ddAMP and ddITP, conformations are almost identical with their nucleoside analogues with sugar ring pucker equilibriating between C3'-endo (approximately 75%) and C2'-endo (approximately 25%). AZTMP and AZTTP on the other hand show significant variations in the conformational behaviour compared with 3'-azido-2',3'-dideoxyribosylthymine (AZT).

NMR studies on the structure of some cyclic and linear antagonists of luteinizing hormone-releasing hormone (LHRH).

The structure of cyclic antagonists of luteinizing hormone-releasing hormone (LHRH), Ac-D-Phe(p-Cl)1-D-Phe(p-Cl)2-D-Trp3-Ser4-c(Asp5-D-Arg6-Leu7- Lys8)-Pro9- D-Ala10-NH2 (I), Ac-D-Phe(p-Cl)1-D-Phe(p-Cl)2-D-Trp3-Ser4-c(Glu5-D-Arg6-Leu7- Lys8)-Pro9-D-Ala10-NH2 (II) and their linear analogues, Ac-D-Phe(p-Cl)1-D- Phe(p-Cl)2-D-Trp3-Ser4-Asp5-D-Arg6-Leu7-Lys8-Pro9-D-++ +Ala10-NH2 (III) and Ac-D-Phe(p-Cl)1-D-Phe(p-Cl)2-D-Trp3-Ser4-Glu5-D-Arg6-Leu7-++ +Lys8-Pro9-D-Ala10-NH2 (IV), have been studied by NMR spectroscopy. The cyclic peptides I and II are more potent antagonists than the corresponding linear peptides in an in vivo assay. All the peptides show propensity of an unusual type II' beta-turn involving residues 3-6.

1H NMR study of the sugar pucker of 2',3'-dideoxynucleosides with anti-human immunodeficiency virus (HIV) activity.

The sugar ring conformations of 2',3'-dideoxyribosyladenine (ddA), 2',3'-dideoxyribosylcytosine (ddC), 2',3'-dideoxyribosylguanine (ddG), 2',3'-dideoxyribosylhypoxanthine (ddI), 3'-azido-2',3'-dideoxyribosylthymine (AZT), 3'-azido-2',3'-dideoxyribosyluracil (AZU) and 3'-fluoro-2',3'-dideoxyribosylthymine (FddT) have been investigated by 1H NMR spectroscopy. While the sugar ring in FddT exists almost totally in C2'-endo geometry, other nucleosides show equilibrium between sugar puckers of C3'-endo family (N-type) and C2'-endo family (S-type). For unsubstituted dideoxynucleosides C3'-endo conformer is favoured (congruent to 75%), whereas for AZT and AZU both the conformers have almost equal populations.

NMR investigation on the structure and conformation of 3'-azido-2',3'-dideoxyribosylthymine (AZT), an inhibitor of the HIV (AIDS virus).

1H and 13C NMR study of 3'-azido-2',3'-dideoxyribosylthymine (AZT), an inhibitor of HIV (human immunodeficiency virus) replication, has been undertaken. Modified Karplus relations have been used to obtain the molecular structure from the indirect coupling constants. NMR results are consistent with an anti glycosyl angle, a sugar pucker with equilibrium between C2'-endo and C3'-endo geometries and a predominantly g+ conformation about C4'-C5' bond.

Deuterium nuclear magnetic resonance spectroscopic study of the fluorescent probe diphenylhexatriene in model membrane systems.

We have investigated the deuterium (2H) nuclear magnetic resonance (NMR) spectra of two 2H-labeled fluorescence probes (trans,trans,trans-1,6-diphenylhexa-1,3,5-trienes, DPHs) incorporated into model lipid bilayer membrane systems at various temperatures. The membranes consisted of multilamellar bilayers of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) containing varying concentrations of cholesterol. The conventional one-order parameter approach often used in the analysis of the NMR data of lipid membranes does not explain the observed temperature variations of the spectral features.

A 13C-NMR study of non-planar distortions in amides.

The technique of 13C-NMR spectroscopy of oriented systems to problems of biological importance has been suggested and used to investigate non-planar distortions in substituted amides--models for peptides. The studies in conjunction with the proton magnetic resonance data on 15N-[13C]methyl[13C]formamide oriented in a nematic solvent provide all the direct dipolar couplings between the interacting nuclei in the system. When the 13C- and the 1H-NMR experiments are performed under non-identical conditions, 22 different direct dipolar couplings are obtained.

N.M.R. of 'oriented' monosubstituted amides--cis and trans N-methyl formamide.

The n.m.r.