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Biomedical subjects

R S Rapaka

Publications and source records attributed to R S Rapaka.

At least 19 recordsLinked to original sources
PubMed1991

Development of delta opioid peptides as nonaddicting analgesics.

Although much effort has been devoted to opioid research since the identification of enkephalins, understanding of the physiological importance and mechanisms of action of endogenous opioids lags behind understanding of opiate alkaloids such as morphine. In recent years, several novel approaches have been refined with promise for the successful development of the long-awaited nonaddicting analgesics that act at the opioid delta receptor. The present communication reviews these efforts.

Analgesics↗
PubMed1990

The molecular basis of cannabinoid activity.

Cannabinoids have been known to exhibit a wide variety of biological effects. Over the past fifty years numerous analogs were synthesized in an attempt to understand the structural requirements for each cannabinoid activity. Only recently, however, some important findings have focused new attention on this field of research. These findings include: (a) The development of novel "non-classical" potent cannabinoid analogs which exhibit similar pharmacological profiles with their "classical" counterparts; (b) The demonstration that there are specific cannabinoid binding sites in cell cultures as well as in mammalian brains; (c) Biophysical studies related to the interactions of cannabinoids with membranes which lead to a better understanding of those molecular properties which are required for cannabinoid activity; (d) Detailed and uniform pharmacological testing on a sizeable number of analogs allowing for a more detailed dissection of the cannabinoid effects and respective "structure activity relationships." The newly increased interest in cannabinoid research opens the door for a better understanding and potential treatment in cases of abuse as well as novel therapeutic opportunities through the design and synthesis of pharmacologically more selective analogs.

Animals↗
PubMed1989

Synthesis and biological properties of 4-norleucine-neuropeptide Y; secondary structure of neuropeptide Y.

Neuropeptide Y (NPY) is a 36 amino acid peptide amide isolated from porcine brain. The NPY analog, 4-norleucine-NPY was synthesized by a solid-phase method and purified to homogeneity in 20% yield by reverse-phase chromatography. Investigation of the biological properties indicated that the analog is an agonist of NPY. Secondary structural analyses revealed that NPY and the analog exhibited predominantly alpha-helical and beta-sheet structures, respectively; however, experiments in trifluoroethanol indicated that the analog has the potential of assuming an alpha-helical structure. Based on circular dichroism (CD), Raman spectroscopy and Chou-Fasman analyses, a model has been proposed for the secondary structure of NPY.

Amino Acid Sequence↗
PubMed1988

Effect of ethanol on the binding of conformationally rigid and labile ligands of opioid receptors to rat brain membranes.

The effect of ethanol on the binding of conformationally rigid and labile ligands for mu and delta opioid receptors to rat brain membranes was determined. The mu ligands used for the studies were [3H]naltrexone and [3H]Tyr-D-Ala-Gly-N-MePhe-Gly-ol (DAGO), and delta ligands used were [3H]Tyr-D-Ser-Gly-Phe-Leu-Thr-OH (DSTLE) and [3H]Tyr-D-Ala-Gly-Phe-Leu (DADLE). The binding of all the opioid ligands was inhibited by ethanol in a concentration-dependent manner. For mu ligands the inhibition was greater for [3H]DAGO binding than for the binding of [3H]naltrexone. For delta ligands, the inhibition by ethanol of the binding of [3H]DADLE was greater than that of [3H]DSTLE. Fourier-transform infrared (FT-IR) spectroscopy was used to determine the conformation of opioid peptides. The data indicated that the conformation of peptides was altered in the presence of ethanol. The results suggest that ethanol inhibits the binding of both mu and delta opioid ligands with greater inhibition observed with conformationally labile ligands. Finally, the alteration in the conformation of the peptide ligands by ethanol, in addition to denaturation of the receptor protein, may also account for the observed inhibitory effect of ethanol on brain opioid receptors.

Animals↗
PubMed1988

Dynorphin A (1-13) peptide NH groups are solvent exposed: FT-IR and 500 MHz 1H NMR spectroscopic evidence.

FT-IR spectroscopic studies of dynorphin A(1-13) in H2O and D2O are utilized to derive the aqueous phase secondary structure of the opioid peptide. Resolution enhancement of the amide I region of dynorphin A(1-13) in H2O revealed a doublet at 1652 cm-1 and 1669 cm-1 which are interpreted as indicative of "unordered" and extended structures. From FT-IR and 1H NMR deuterium exchange studies, the peptide NH groups appeared to be solvent accessible which is suggestive of an essentially extended structure with aperiodically interwoven "unordered" structure. The results are consistent with Raman Spectroscopic (Rapaka et al., (1987) Int. J. Peptide Protein Res. 30:284-287) and 2D NMR studies (Huang et al. submitted), from our laboratory.

Dynorphins↗
PubMed1987

A 500 MHz 1H NMR spectroscopic study of Met5-enkephalinamide in aqueous solution: ethanol induced conformational changes.

An analysis of spin coupling constants, less than 3J greater than C alpha H-NH, from a high resolution 500 MHz 1H NMR study of [Met5]-enkephalinamide in aqueous solution, suggested that beta-sheet structure is the likely conformer. The effect of ethanol on the conformation of [Met5]-enkephalinamide in aqueous solution was investigated. From the upfield drift of observed chemical shifts and changes in coupling constants, especially of the amide NH resonances, it is concluded that ethanol disrupts the conformation possibly by influencing the hydrogen bonding. The above observation is consistent with a recent study of the ethanol induced conformational changes occurring in [Met5]enkephalinamide [Rapaka, R.S. et al. (1986) Life Sciences 39, 837-842].

Enkephalin, Methionine↗
PubMed1987

Influence of tablet dissolution on furosemide bioavailability: a bioequivalence study.

In order to evaluate the in vitro dissolution and in vivo bioavailability relationship for furosemide, a bioequivalence study was carried out. Furosemide (40 mg) was administered orally to 12 normal volunteers in a 6 x 6 crossover design using six products (five tablets and one solution) obtained from three pharmaceutical companies. Plasma and urine concentrations of furosemide were quantitated by high-performance liquid chromatography (HPLC). Plasma furosemide profiles were analyzed by non-compartmental methods. Compared to the oral solution, all of the formulations exhibited lower peak furosemide concentrations, longer mean residence times, and, in some cases, diminished bioavailability (range, 66-96%). Similar results were obtained when the reference product (a rapidly dissolving tablet) was used as the standard. All of the products failed the 75/75 rule when compared to either reference standard, apparently because of large intersubject variability. The total amount of furosemide excreted in urine could be associated with the percentage drug dissolved (in vitro) at 30 min. The pH 5.6 dissolution medium (compared to pH 4.6) appears to be an appropriate test medium for assuring batch uniformity and bioequivalence of furosemide products.

Administration, Oral↗
PubMed1986

Molecular mechanics studies of dermorphin.

Molecular mechanical simulations have been carried out on dermorphin. Presence of D-Ala2 at the N-terminus and L-Pro6 residue at the C-terminus indicated the probability of beta-turns. From the stereochemical considerations, three types- II', III' and V' - for the beta-turn at the N-terminus of the peptide and two types-I and III- for the C-terminus side of the peptide are possible. In our molecular mechanics calculations, we considered six folded and one extended conformations for dermorphin to asses the relative stabilities. Three of the six folded conformations are lower in energy and have the following general feature-similar in energy, three hydrogen bonds, semirigid beta-sheet segment and favorable Tyr1-Tyr5 interaction. The presence of beta-sheet structure might play a role in mu-receptor selective interaction of dermorphin.

Analgesics, Opioid↗
PubMed1986

Ethanol induced conformational changes of the peptide ligands for the opioid receptors and their relevance to receptor interaction.

The FT-IR (Fourier Transform Infrared) Spectrum of [Met 5]-enkephalinamide in aqueous solution shows the presence of both the beta-turn and beta-sheet conformations. The beta-turn and beta-sheet conformations of enkephalins have been proposed to play a role in receptor selectivity. Addition of ethanol alters these secondary structural features and hence the effect of ethanol on ligand-receptor interaction may be mediated primarily through conformational changes of the ligand rather than those of the receptor.

Animals↗