Design, synthesis, biology, and conformations of bicyclic alpha-melanotropin analogues.

Seven side chain-constrained bicyclic alpha-melanotropin (alpha-MSH) analogues were designed and synthesized, their conformations analyzed, and their biological properties examined in the frog skin and lizard skin bioassays. The structure of these analogues is based on the central sequence Ac-Cys4-Xaa5-His6-DPhe7-Arg8-Trp9-Cys10-Lys11 -NH2 (Xaa5 = Asp or Glu) and has been extended on the N-terminal with the amino acids Ser1-Tyr2-Ser3 and on the C-terminal with Pro12-Val13 to more closely resemble the native hormone alpha-MSH. The analogue Ac-Cys4-Asp5-His6-DPhe7-Arg8-Trp9-Lys10-Cys11 -NH2 also was synthesized, and its conformational and biological properties were examined.

Sonoelasticity imaging of prostate cancer: in vitro results.

Purpose: To compare sonoelasticity imaging versus ultrasound (US) in detection of prostate cancer.

Materials And Methods: Sonoelasticity imaging and US were performed on 10 prostatectomy specimens in which cancer was detected at previous biopsy. Six patients had no palpable lesions at digital rectal examination.

The molecular biology of the flavin-containing monooxygenases of man.

cDNA clones encoding five distinct members of the FMO family of man (FMOs 1, 2, 3, 4 and 5) were isolated by a combination of library screening and reverse transcription-polymerase chain reaction techniques. The deduced amino acid sequences of the human FMOs have 82-87% identity with their known orthologues in other mammal but only 51-57% similarity to each other. The hydropathy profiles of the proteins are very similar.

Coat color darkening in a dog in response to a potent melanotropic peptide.

Analogues of a melanocyte-stimulating hormone (alpha-MSH) have been documented to be effective in inducing integumental melanogenesis in several species. These melanotropin analogues are more potent than the natural hormone and have prolonged biological activity, without apparent teratogenic or other toxic effects, at least in rodents. In a pilot study, a cyclic alpha-MSH analogue, Ac-[Nle4, Asp5, D-Phe7, Lys10] alpha-MSH4-10-NH2, was administered SC to a dog at a dose of 1 mg of analogue in 1 ml of 0.

Multivalent melanotropic peptide and fluorescent macromolecular conjugates: new reagents for characterization of melanotropin receptors.

Radioreceptor binding studies have documented the presence of melanotropin receptors on some but not all of the various human melanoma cell lines that have been studied. Using a newly developed class of multivalent fluorescent melanotropin-macromolecular conjugates, we have demonstrated for the first time the presence of specific melanotropin receptors on all of the melanoma cell lines, both mouse and human, melanotic as well as amelanotic, that were investigated. The conjugates developed by us consisted of multiple copies of both a potent melanotropin analogue and a fluorophore, both arranged in a pendent fashion on a biologically inert macromolecule.

Chorda tympani nerve injury following inferior alveolar injection: a review of two cases.

Permanent nerve injury following the injection of local anesthetic during dental procedures is rare. Two cases of chorda tympani nerve injury shown by ageusia are presented.

A comparison of HPLC and bioassay methods for plasma melanotan-II (MT-II) determination: application to a pharmacokinetic study in rats.

The pharmacokinetic profile of the melanotropic peptide, melanotan-II (MT-II), was determined in rats following a 0.3 mg kg-1 intravenous dose. Regression analysis of the plasma MT-II concentrations determined using HPLC and bioassay methods indicated the existence of a significant linear correlation (r = 0.

Enantiospecific analysis: applications in bioanalysis and metabolism.

Enantiospecific analysis has a significant role in modern drug development from discovery-chemistry to the clinical evaluation of novel compounds. Chromatographic techniques, involving the use of either chiral derivatizing agents or chiral stationary phases, represent the most commonly used approaches to enantiospecific analysis. The advantages and limitations of these two techniques are examined using the analysis of the enantiomers of the 2-arylpropionic acids (tiaprofenic acid and ibuprofen) and the chiral N-oxides of N-ethyl-N-methylaniline and pargyline, as representative examples for each approach.

Identification of a deoxyguanosine-malondialdehyde adduct in rat and human urine.

In an ongoing study, rat and human urine have been examined for the presence of malondialdehyde (MDA) derivatives as indicators of the nature of lipid peroxidative damage caused by this compound in vivo. MDA in urine was found to be present mainly in the form of two lysine adducts, one acetylated and the other unacetylated, reflecting in vivo reactions with tissue proteins. Two minor metabolites were identified as adducts with the phospholipid bases serine and ethanolamine and a third one as an adduct with the nucleic acid base guanine.

Dialysis-associated spondylarthropathy. Report of 10 cases.

Ten patients undergoing long-term renal dialysis for end-stage renal failure developed a destructive, non-infectious spondylarthropathy. All 10 patients had biopsy-proven dialysis-associated spondylarthropathy and subsequent spinal instability secondary to beta 2-microglobulin deposition in the vertebrae, intervertebral disc spaces, and support structures of the spine. Nine patients had cervical spinal instability and one had thoracolumbar spinal instability, with resultant neural compression.

Asymmetric metabolic N-oxidation of N-ethyl-N-methylaniline by purified flavin-containing monooxygenase.

The prochiral tertiary amine N-ethyl-N-methylaniline (EMA) is known to be metabolically N-oxygenated in vitro with microsomal preparations. This biotransformation is thought to be mediated predominantly by the flavin-containing monooxygenase (FMO) enzyme system. Microsomal N-oxygenation of EMA is known to be stereoselective and varies between species.

Species variability in the stereoselective N-oxidation of pargyline.

The monoamine oxidase inhibitor pargyline (N-benzyl-N-methyl-2-propynylamine) is known to undergo extensive in vitro microsomal N-oxidation, thought to be mediated predominantly by the flavin-containing monooxygenase (FMO) enzyme system. Formation of the pargyline N-oxide (PNO) metabolite creates a chiral nitrogen centre and thus asymmetric oxidation is possible. This study describes a reverse-phase high-performance liquid chromatographic (HPLC) method for the quantitation of PNO and a chiral-phase HPLC method for the determination of the enantiomeric ratio of PNO.

The actions of melanin-concentrating hormone (MCH) on passive avoidance in rats: a preliminary study.

Melanin-concentrating hormone (MCH) is a hepadecapeptide hormone that is synthesized in the CNS and is responsible for melanosome aggregation in the teleost fish. Recent evidence suggests that this peptide hormone has a unique distribution in the mammalian brain, which leads to the speculation that it may serve as a neuromodulator. The present study was undertaken to explore the comparative effects of MCH to those of alpha-melanocyte-stimulating Hormone (MSH) (a neuropeptide that is known to influence learning) on the rate of extinction of a passive avoidance response in rats.

Discovery of an alpha-melanotropin antagonist effective in vivo.

A hybrid analogue, H-His-D-Arg-Ala-Trp-D-Phe-Lys-NH2, was designed based upon the primary structures of a growth hormone-releasing peptide analogue, [His1,Lys6]GHRP, and the MSH fragment, Ac-alpha-MSH(6-11)-NH2. In vitro studies demonstrated the alpha-MSH antagonistic efficacy of the analogue in the lizards Sceloporus jarrovii and Urosaurus ornatus. In live white background-adapted S.

Structure-activity correlations of melanotropin peptides in model lipids by tryptophan fluorescence studies.

Steady-state and time-resolved fluorescence spectroscopy were employed in the study of the structure and interactions of alpha-MSH (alpha-melanocyte-stimulating hormone) and its analogs, [Nle4,D-Phe7]-alpha-MSH (MSH-I) and Ac-[Nle4,Asp5,D-Phe7,Lys10]-alpha-MSH(4-10)-NH2 (MSH-II). In aqueous buffer, the fluorescence parameters of the single tryptophan of alpha-MSH and MSH-I were similar and did not allow any distinction between these molecules. On the other hand, the tryptophan fluorescence of MSH-II was notably different, reflecting its cyclic lactam turn structure.

A comparative evaluation of thiobarbituric acid methods for the determination of malondialdehyde in biological materials.

A comparative evaluation was made of the conventional spectrophotometric procedure and three published high performance liquid chromatographic (HPLC) procedures for the determination of malondialdehyde (MDA) as the thiobarbituric acid (TBA) derivative when applied to liver, fish meal, serum, and urine. Except for urine, spectrophotometric analysis overestimated MDA content. Purification of the TBA-MDA complex obtained from liver and fish meal on reverse phase cartridges was found to entail a loss of complex bound to residual peptides in the trichloracetic acid (TCA) extract.

Stereoselective microsomal N-oxidation of N-ethyl-N-methylaniline.

The stereoselectivity of metabolic N-oxidation of N-ethyl-N-methylaniline (EMA) was investigated in vitro following incubation of the compound (1mM) with fortified hepatic microsomal preparations of both male Wistar rats and New Zealand White (NZW) rabbits. The major metabolites in both species were found to be N-ethylaniline, N-methylaniline and EMA N-oxide. Chromatographic resolution of the N-oxide enantiomers was achieved using a Chiralcel OD stationary-phase with a mobile-phase of hexane:ethanol (98:2, v/v).

Substituted benzamides with conformationally restricted side chains. 5. Azabicyclo[x.y.z] derivatives as 5-HT4 receptor agonists and gastric motility stimulants.

The syntheses of benzamides containing azabicyclo[x.y.z] side chains and their 5-HT4 receptor agonist and 5-HT3 receptor antagonist properties are described.