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To further evaluate elements that could contribute to the 3D topographical structure of γ-MSH, we have systematically designed a group of linear γ-MSH analogues and evaluated their biological activities:  without a N-terminal acetyl, with and without a C-terminal amide, with Nle³, with l- or d-Phe⁶ or d-Nal(2‘)⁶, and with d-Trp⁸ or d-Nal(2‘)⁸. It was found that changing the C-terminal acid in γ-MSH to an amide and replacing Met with Nle leads to increased binding affinities at all four subtypes of melanocortin receptors (10−100 fold). Substitution of Trp⁸ with d-Nal(2‘)⁸ and Phe⁶ with d-Phe⁶ in γ-MSH-NH2 forms a selective antagonist for the hMC3R, whereas, substitution of Phe⁶ with d-Nal(2‘)⁶ and replacing Trp⁸ with d-Trp⁸ at γ-MSH-NH2 yields a selective partial agonist for the hMC1R. Finally, substitution of His⁵ with Pro⁵ and Trp⁸ with d-Nal(2‘)⁸ in γ-MSH-NH2 leads to a highly potent and selective agonist for the hMC1R. Molecular modeling showed that, at the C-terminal of Nle³-γ-MSH-NH2, there is a reverse-turn-like structure, suggesting that there might be a secondary binding site involved in ligand−receptor interaction for γ-MSH analogues that may explain the enhanced binding affinities of the Nle³-γ-MSH-NH2 analogues. Our results indicate that increasing the hydrophobicity and replacing Phe⁶ and Trp⁸ with bulkier aromatic amino acid residues is very important for selectivity of α-MSH/γ-MSH hybrids for hMCRs.

It has been shown by extensive studies that melanotropin bioactivities are critically dependent on the core or central tetrapeptide sequence, His-Phe-Arg-Trp, and in α-MSH it has been demonstrated further that a reverse-turn type conformation exists at this pharmacophore. To probe the receptor active conformation of the pharmacophore His-Phe-Arg-Trp in γ-MSH, two different series of γ-MSH analogues have been designed and synthesized and their biological activities determined at hMC3R, hMC4R, and hMC5R. The 1st series consists of a cyclic scan using different disulfides or lactam bridges. It was found that cyclization of the native γ-MSH around the highly conserved sequence can lead to shifts in affinity and selectivity for hMC4R instead of the hMC3R as seen in the native peptide. Furthermore, a 23-membered ring is desirable for potency (e.g., analogues 6 and 10) whereas a 26-membered ring (analogue 1, H-Tyr-Val-c[Cys-Gly-His-Phe-Arg-Trp-Cys]-Arg-Phe-Gly-NH2 with Gly⁴) is more important for selectivity. The 2nd series is made of d-2-naphthylalanine (d-Nal(2‘)) scan of the γ-MSH sequence at position 6 and 8 and the replacement of His⁵ with Pro (analogue 13). Analogue 12, H-Tyr-Val-Nle-Gly-His-Phe-Arg-d-Nal(2‘)-Asp-Arg-Phe-Gly-NH2, is a potent and selective antagonist at the hMC4R, and analogue 15, H-Tyr-Val-Nle-Gly-Aib-Phe-Arg-d-Nal(2‘)-Asp-Arg-Phe-Gly-NH2, is a highly selective and potent agonist of the hMC5R. A most promising analogue is 13, H-Tyr-Val-Nle-Gly-Pro-d-Nal(2‘)-Arg-Trp-Asp-Arg-Phe-Gly-NH2, which is a very potent agonist of the hMC4R, and this analogue can be further evaluated for feeding behavior and the regulation of fat stores.

It has been shown by extensive studies that α-MSH bioactivity is critically dependent on the core or central tetrapeptide sequence, His-Phe-Arg-Trp, however with poor selectivity for the human MC3R-MC5R. The structure−activity relationships study here is aimed at identifying lead structures or templates of this core sequence by the use of different conformational constraints that might impart changes in its topography and thus promote differences in potency and selectivity at these receptors. Our peptide library consists of a novel series of cyclic α-MSH analogues that have disulfide bridges between Cys or Cys-like residues at positions 4 and 10, giving rise to 23-membered rings fused at the C-terminal end with the C-terminal fragment of β-MSH (Pro-Pro-Lys-Asp). While such constraints of the peptide backbone with disulfide bridges of different chirality affect potency and selectivity at these receptors, further changes in the hydrophobicity at position 7 with either a d-Phe or d-Nal(2‘) and replacement of a His with a Pro in position 6 cause additional effects. Thus, the most interesting lead compounds that emerged from this study are (1) compound 5, Ac-c[Cys-Glu-His-d-Phe-Arg-Trp-d-Cys]-Pro-Pro-Lys-Asp-NH2 (IC50 = 10 nM), which is the first potent and highly selective antagonist ligand for the hMC5R (560-fold vs the MC3R and 1000-fold vs the MC4R); (2) compound 7, Ac-c[Cys-Glu-Pro-d-Nal(2‘)-Arg-Trp-Cys]-Pro-Pro-Lys-Asp-NH2 (IC50 = 31 nM), which is a highly selective antagonist analogue for the MC3R (560-fold vs the hMC4R and about 3000-fold vs the hMC5R; and (3) compound 9, Ac-c[Pen-Glu-His-d-Nal(2‘)-Arg-Trp-Cys]-Pro-Pro-Lys-Asp-NH2 (IC50 = 3 nM), which is more potent than 7 at the MC3R but not as selective.

A series of easy to prepare organic salt based on imidazole derivatives and cyclobutane-1,1-dicarboxylic acid have been studied for their gelation behavior after it was found that imidazolium hydrogen cyclobutane-1,1-dicarboxylate (1) can harden few organic liquids. 1 forms remarkably stable gel (remains intact for several months in an open container, gel dissociation temp TGel = 66 °C) with nitrobenzene at a very low concentration of 0.137 wt %, whereas bis-imidazolium cyclobutane-1,1-dicarboxylate (2) resulted in a weak and unstable gel with nitrobenzene, indicating the importance of the free COOH group in 1 in gel formation. Molecular packing in the primary assembly unit (fibers) of xerogel of 1/nitrobenzene is successfully established based on single-crystal X-ray and X-ray powder diffraction data. The morph responsible for gel formation of 1 with nitrobenzene is found to be different from that of its xerogel. Substitution on the imidazole moiety results in nongelators.

Luminescent Y₂O₂S : Eu3+ nanoceramics having an average particle size of 20 nm has been prepared through a gel–polymer thermolysis process employing a urea–formaldehyde resin. In this nanocrystalline system, large blue shifts (in relation to the bulk system) of ~5000 cm−1 and ~2000 cm−1 in the photoluminescence excitation bands corresponding to the excitonic region and the Eu3+–ligand charge transfer region respectively have been observed. These may be explained by considering possible size dependent changes in optical electronegativity and quantum confinement effects occurring in this large bandgap semiconductor system.

We have designed and synthesized several novel cyclic SHU9119 analogues (Ac-Nle⁴-[Asp⁵-His⁶-DNal(2‘)⁷-Arg⁸-Trp⁹-Lys¹⁰]-NH2) modified in position 6 with nonconventional amino acids. SHU9119 is a high affinity nonselective antagonist at hMC3R and hMC4R with potent agonist activity at hMC1R and hMC5R. We measured the binding affinity and agonist potency of the novel analogues at cloned hMC3R, hMC4R, and hMC5R receptors and identified several selective, high affinity hMC3R and hMC4R antagonists. Compound 4 containing Che substitution in position 6 is a high affinity hMC4R antagonist (IC50 = 0.48 nM) with 100-fold selectivity over hMC3R antagonist. Analogue 7 with a Cpe substitution in position 6 is a high affinity hMC4R antagonist (IC50 = 0.51 nM) with a 200-fold selectivity vs the hMC3R. Interestingly, analogue 9 with an Acpc residue in position 6 is a high affinity hMC3R antagonist (IC50 = 2.5 nM) with 100-fold selectivity vs the hMC4R antagonist based on its binding affinities. This compound represents the first cyclic lactam antagonist with high selectivity for the hMC3R vs hMC4R. To understand the possible structural basis responsible for selectivity of these peptides at hMCR3 and hMCR4, we have carried out a molecular modeling study in order to examine the conformational properties of the cyclic peptides modified in position 6 with conformationally restricted amino acids.

Cataract is the leading cause of blindness worldwide. It is a multifactorial disease primarily associated with oxidative stress produced by free radicals. The protection offered by various antioxidants in cataract development is well established. Polyphenolic compounds present in green tea (Camellia sinensis)are reported to possess antioxidant property in various pathological conditions. The present study was undertaken to evaluate the anticataract potential of green tea leaf (GTL) extract in the development of lens opacification. Enucleated rat lenses were randomly divided into normal, control and treated groups and incubated for 24 h at 37°C. Oxidative stress was induced by sodium selenite in the culture medium of the two groups (except the normal group). The medium of the treated group was additionally supplemented with GTL extract. After incubation, lenses were subjected to glutathione and malondialdehyde estimation. Enzyme activity of superoxide dismutase, catalase and glutathione peroxidase was also measured in different sets of the experiment. In vivo cataract was induced in 9-day-old rat pups of both control and treated groups by a single subcutaneous injection of sodium selenite. The treated pups were injected GTL extract intraperitoneally prior to selenite challenge and continued for 2 consecutive days thereafter. Cataract incidence was evaluated on 16th postnatal day by slit lamp examination. There was positive modulation of biochemical parameters in the organ culture study. Green tea was also found to reduce the incidence of selenite cataract in vivo. The results suggest that green tea possesses significant anticataract potential and acts primarily by preserving the antioxidant defense system.

In an effort to develop highly selective and potent agonists and/or antagonists for the hMC3 and hMC4 receptors, a new approach involving the use of linker arms and a backbone to side chain cyclization strategy was employed. Three key analogues were identified to have the required selectivity and potency at the hMC3 or hMC4 receptors, implicated to play pivotal roles in energy homeostasis and other biological effects. The novel cyclic peptide (O)C-CH2-CH2-C(O)-c-[His⁶-D-Phe⁷-Arg⁸-Trp⁹-Lys¹⁰]-NH2 (1) was found to be a highly selective and potent agonist of the hMC4 receptor. Structure−activity studies have shown that replacing the succinyl linker arm of 1 by an o-phthalic acid group and substituting a D-Nal(2‘)⁷ residue in place of D-Phe⁷ results in a potent antagonist 7 at the hMC4 receptor. Furthermore, increasing the 23-membered lactam ring of 1 by one carbon atom (succinyl → glutaric acid linker) gives a highly selective and potent antagonist 9 for the hMC3 receptor. Analogues 1, 7, and 9 therefore represent the first examples of a class of cyclic melanotropin ligands with high selectivity and defined biological activities at the physiologically important hMC3 and hMC4 receptors.

Glucagon is a crucial hormone in glucose homeostasis and hence has great potential for application to research which seeks to understand its role in normal and diabetic states. Furthermore, antagonists of glucagon, acting at the glucagon receptor, have numerous applications for studying glucagon's role in various physiological functions, and as a potential drug for the treatment of diabetes and diabetic syndromes. In this paper we will discuss research done over the last decade or so which has led to development of 1) the first pure glucagon receptor antagonists which have no partial agonist activity even at high concentrations and under conditions where the cAMP signal is greatly enhanced; 2) systematic studies of glucagon structure-function which have greatly extended our knowledge of those amino acids in glucagon which are most responsible for high affinity binding; 3) residues most important for agonist and for antagonist biological activities; 4) the first highly truncated analogues of glucagon which possess high affinity for the glucagon receptor and are antagonists; 5) cyclic analogues of glucagon which provide insight in the role of α-helix and β-turn structures in the binding affinity of glucagon to its receptor; 6) the first glucagon analogues with subnanomolar binding at the glucagon receptor; and 7) insights into those stereostructural properties which are different in agonist and antagonist analogues. We also discuss conformational studies which have been performed on glucagon and its agonist and antagonist analogues using various biophysical methods including NMR, X-ray crystallography and circular dichroism spectroscopy. Finally we briefly discuss the uses of glucagon analogues, especially glucagon antagonists, in examining the mechanisms and roles of glucagon in normal and diabetic states, and some aspects of the molecular biology of the glucagon receptor.

Mechanical circulatory support (MCS) is increasingly used after cardiotomy in children when conventional medical treatment fails. Poor overall survival and long-term outcome have been reported. We report our experience of post-cardiotomy MCS using a conventional bypass circuit.

In search for the bioactive conformation of glucagon, “positional cyclization scanning” was used to determine secondary structures of glucagon required for maximal interaction with the glucagon receptor. Because glucagon is flexible in nature, its bioactive conformation is not known except for an amphiphilic helical conformation at the C-terminal region. To understand the conformational requirement for the N-terminal region that appears to be essential for signal transduction, a series of glucagon analogues conformationally constrained by disulfide or lactam bridges have been designed and synthesized. The conformational restrictions via disulfide bridges between cysteine i and cysteine i + 5, or lactam bridges between lysine i and glutamic acid i + 4, were applied to induce and stabilize certain corresponding secondary structures. The results from the binding assays showed that all the cyclic analogues with disulfide bridges bound to the receptor with significantly reduced binding affinities compared to their linear counterparts. On the contrary, glucagon analogues containing lactam bridges, in particular, c[Lys⁵, Glu⁹]glucagon amide (10) and c[Lys¹⁷, Glu²¹]glucagon amide (14), demonstrated more than 7-fold increased receptor binding affinities than native glucagon. These results suggest that the bioactive conformation of glucagon may adopt a helical conformation at the N-terminal region as well as the C-terminal region, which was not evident from earlier biophysical studies of glucagon.

In pursuit of truncated glucagon analogues that can interact with the glucagon receptor with substantial binding affinity, 23 truncated glucagon analogues have been designed and synthesized. These truncated analogues consist of several fragments of glucagon with 11 or 12 amino acid residues (1−4), conformationally constrained analogues containing the sequence of the middle region of glucagon (5−15), and truncated analogues containing the sequence of the C-terminal region (16−23). Biological assays of these analogues showed that the truncated glucagon analogues with the sequence of the C-terminal region possess significantly better binding affinity compared to the truncated analogues with the sequence of the middle region, and these analogues (17−23) demonstrated potent antagonistic activity (pA2 values between 6.5 and 7.5). On the basis of these results, it can be suggested that glucagon interacts with its receptor with two hydrophobic patches located in the middle and the C-terminal regions of glucagon, and both hydrophobic patches are necessary for significant receptor recognition. These two hydrophobic binding motifs, located in two different regions of glucagon, appear to be the reason why the earlier attempts to obtain truncated analogues with good binding affinity did not result in any success. Long peptide hormones such as glucagon seem to require more than one binding pocket on the receptors for maximal interaction.

The optimal management of tetralogy of Fallot is still under debate, particularly with respect to surgical approach and the age of operation. In recent times a transatrial-transpulmonary approach and primary repair in younger patients is favoured. The purpose of the present study was to analyze the result of our current surgical management by assessing the perioperative and intermediate term follow up in order to define the optimal strategy and timing of operation for our institution.

Glucagon was systematically modified by forming lactam bridges within the central region of the molecule to give conformationally constrained cyclic analogues. Six cyclic glucagon analogues have been designed and synthesized. They are c[Asp⁹,Lys¹²][Lys^17,18,Glu²¹]glucagon-NH2 (1), c[Asp⁹,Lys¹²]glucagon-NH2 (2), c[Lys¹²,Asp¹⁵]glucagon-NH2 (3), c[Asp¹⁵,Lys¹⁸]glucagon-NH2 (4), [Lys¹⁷-c[Lys¹⁸,Glu²¹]glucagon-NH2 (5), and c[Lys¹²,Asp²¹]glucagon-NH2 (6). The receptor binding potencies and receptor second messenger activities were determined by radio-receptor binding assays and adenylate cyclase assays, respectively, using rat liver plasma membranes. Most interestingly, analogues 1, 2, 3, and 4 were antagonists of glucagon stimulated adenylate cyclase activity, whereas analogues 5 and 6 were partial agonists in the functional assay. All of the cyclic analogues were found to have reduced binding potencies relative to glucagon. The structural features that might be responsible for these effects were studied using circular dichroism spectroscopy and molecular modeling. These results demonstrated the significant modulations of both receptor binding affinity and transduction (adenylate cyclase activity) that can accompany regional conformational constraints even in larger polypeptide ligands. These studies suggest that the entire molecular conformation, including the flexible middle portion, is important for molecular recognition and transduction at the hepatic glucagon receptor.

The electronic, magnetic, optical and redox properties of conjugated polymers are greatly influenced by structure, electronegativity, solvation and orientation of a counter ion. The doping by counter ion not only creates a band structure but also stabilizes localized bound states to impart unusual optical and magnetic properties to macromolecular system. When the polymer is in contact with solution of an electrolyte, counter ion tends to be solvated and mobile in the polymer phase, imparting it a property of ion exchange membrane. Here we briefly summarize the influence of anion on properties and electrochemical behaviour of polyaniline and polypyrrole.

Treatment of intact hepatocytes with glucagon, TH-glucagon [(1-N-alpha-trinitrophenylhistidine, 12-homoarginine]glucagon), angiotensin or vasopressin led to a rapid time- and dose-dependent loss of the glucagon-stimulated response of the adenylate cyclase activity seen in membrane fractions isolated from these cells. Intracellular cyclic AMP concentrations were only elevated with glucagon. All ligands were capable of causing both desensitization/loss of glucagon-stimulated adenylate cyclase activity and stimulation of inositol phospholipid metabolism in the intact hepatocytes. Maximally effective doses of angiotensin precluded any further inhibition/desensitizing action when either glucagon or TH-glucagon was subsequently added to these intact cells, as has been shown previously for the phorbol ester TPA (12-O-tetradecanoylphorbol 13-acetate) [Heyworth, Wilson, Gawler & Houslay (1985) FEBS Lett. 187, 196-200]. Treatment of intact hepatocytes with these various ligands caused a selective loss of the glucagon-stimulated adenylate cyclase activity in a washed membrane fraction and did not alter the basal, GTP-, NaF- and forskolin-stimulated responses. Angiotensin failed to inhibit glucagon-stimulated adenylate cyclase activity when added directly to a washed membrane fraction from control cells. Glucagon GR2 receptor-stimulated adenylate cyclase is suggested to undergo desensitization/uncoupling through a cyclic AMP-independent process, which involves the stimulation of inositol phospholipid metabolism by glucagon acting through GR1 receptors. This action can be mimicked by other hormones which act on the liver to stimulate inositol phospholipid metabolism. As the phorbol ester TPA also mimics this process, it is proposed that protein kinase C activation plays a pivotal role in the molecular mechanism of desensitization of glucagon-stimulated adenylate cyclase. The site of the lesion in desensitization is shown to be at the level of coupling between the glucagon receptor and the stimulatory guanine nucleotide regulatory protein Gs, and it is suggested that one or both of these components may provide a target for phosphorylation by protein kinase C.

The results of investigations of the chemical and electrochemical polymerization of aniline in sulphamic acid medium and its characterization by electrochemical and spectroscopic techniques are presented. The investigations reveal that sulphamic acid medium affects, not only the polymerization process, but also its electrochemical characteristics.

The electrochemical oxidation of Co2+ to Co3+ in acetic acid medium has been effectively and efficiently carried out in a divided cell at a graphite electrode with a current efficiency of 92% using a porous pot as separator. Using Co3+ acetate, oxidation of toluene to benzyl acetate was successfully carried out.

We have designed and synthesized eight compounds 2−9 which incorporate various amino acid residues in positions 17, 18, and 21 of the glucagon molecule:  2, [Lys¹⁷]glucagon amide; 3, [Lys¹⁸]glucagon amide; 4, [Nle¹⁷,Lys¹⁸,Glu²¹]glucagon amide; 5, [Orn^17,18, Glu²¹]glucagon amide; 6, [d-Arg¹⁷]glucagon; 7, [d-Arg¹⁸]glucagon; 8, [d-Phe¹⁷]glucagon; and 9, [d-Phe¹⁸]glucagon. Compared to glucagon (IC50 = 1.5 nM), analogues 2−9 were found to have binding affinity IC50 values (in nM) of 0.7, 4.1, 1.0, 2.0, 5.0, 25.0, 43.0, and 32.0, respectively. When these compounds were tested for their ability to stimulate adenylate cyclase (AC) activity, they were found to be full or partial agonists having maximum stimulation values of 100, 100, 100, 100, 87, 78, 94, and 100%, respectively. On the basis of the X-ray crystal structure of [Lys^17,18,Glu²¹]glucagon amide reported here, the ability to form a salt bridge between Lys¹⁸ and Glu²¹ is probably key to their increased binding and second messenger activities. Among the eight analogues synthesized here, only analogue 4 preserves the ability to form a salt bridge between Lys¹⁸ and Glu²¹. However, since these modifications are minor they do not seem to change the amphiphilic character of the C-terminus, allowing these analogues to reach 78−100% stimulation in the adenylate cyclase assay. Biological data from analogues 6−9 supports the idea that position 18 of glucagon may influence binding only, while position 17 may influence both receptor recognition and transduction.

The role of position 10 in the β-turn region of glucagon was investigated by substituting chiral constrained amino acids and other modifications in the N-terminal region. A series of glucagon analogues have been designed and synthesized by incorporating β-methylphenylalanine isomers (2S,3S, 2S,3R, 2R,3R, and 2R,3S) at position 10 in order to explore the structural and topographical requirements of the glucagon receptor, and, in addition, utilizing previous studies which indicated that antagonism could be enhanced by modifications (des-His¹, Glu⁹) and a bulky group at position 5. The structures of the new analogues are as follows:  [des-His¹,Tyr⁵,Glu⁹]glucagon-NH2 (II), [des-His¹,Tyr⁵,Glu⁹,Phe¹⁰]glucagon-NH2 (III), [des-His¹,Tyr⁵,Glu⁹,Ala¹⁰]glucagon-NH2 (IV), [des-His¹,Tyr⁵,Glu⁹,(2S,3R)-β-MePhe¹⁰]glucagon-NH2 (V), [des-His¹,Tyr⁵,Glu⁹,(2S,3S)-β-MePhe¹⁰]glucagon-NH2 (VI), [des-His¹,Tyr⁵,Glu⁹,d-Tyr¹⁰]glucagon-NH2 (VII), [des-His¹,Tyr⁵,Glu⁹,d-Phe¹⁰]glucagon-NH2 (VIII), [des-His¹,Tyr⁵,Glu⁹,d-Ala¹⁰]glucagon-NH2 (IX), [des-His¹,Tyr⁵,Glu⁹,(2R,3R)-β-MePhe¹⁰]glucagon-NH2 (X), and [des-His¹,Tyr⁵,Glu⁹,(2R,3S)-β-MePhe¹⁰]glucagon-NH2 (XI). These analogues led to dramatically different changes in in vitro binding affinities for glucagon receptors. Their receptor binding potencies IC50 values (nM) are 2.3 (II), 4.1 (III), 395.0 (IV), 10.0 (V), 170.0 (VI), 74.0 (VII), 34.5 (VIII), 510.0 (IX), 120.0 (X), and 180.0 (XI). Analogues II, III, V, VI, and XI were found to be weak partial agonists/partial antagonists with maximum stimulation between 5%−9%, while the other compounds (IV and VII−X) were antagonists unable to activate the adenylate cyclase system even at concentrations as high as 10^-5 M. In competition experiments, all of the analogues caused a right shift of the glucagon-stimulated adenylate cyclase dose−response curve. The pA2 values were 6.60 (II), 6.85 (III), 6.20 (IV), 6.20 (V), 6.10 (VI), 6.50 (VII), 6.20 (VIII), 5.85 (IX), 6.20 (X), and 6.00 (XI). Putative topographical requirements of the glucagon receptor for the aromatic side chain conformation in position 10 of glucagon antagonists are discussed.

Extensive evidence gathered from structure-activity relationship analysis has identified and confirmed specific positions in the glucagon sequence that are important either for binding to its receptor or for signal transduction. Fifteen glucagon analogues have been designed and synthesized by incorporating structural changes in the N-terminal region of glucagon, in particular histidine-1, phenylalanine-6, and aspartic acid-9. This investigation was conducted to study the role of phenylalanine at position 6 on the glucagon mechanism of action. These glucagon analogues have been made by either deleting or substituting hydrophobic groups, hydrophilic groups, aromatic amino acids, or a d-phenylalanine residue at this position. The structures of the new analogues are as follows:  [des-His¹,des-Phe⁶,Glu⁹]glucagon-NH2 (1); [des-His¹,Ala⁶,Glu⁹]glucagon-NH2 (2); [des-His¹,Tyr⁶,Glu⁹]glucagon-NH2 (3); [des-His¹,Trp⁶,Glu⁹]glucagon-NH2 (4); [des-His¹,d-Phe⁶,Glu⁹]glucagon-NH2 (5); [des-His¹,Nle⁶,Glu⁹]glucagon-NH2 (6); [des-His¹,Asp⁶,Glu⁹]glucagon-NH2 (7); [des-His¹,des-Gly⁴,Glu⁹]glucagon-NH2 (8); [desPhe⁶,Glu⁹]glucagon-NH2 (9); [des-Phe⁶]glucagon-NH2 (10); [des-His¹,des-Phe⁶]glucagon-NH2 (11); [des-His¹,des-Phe⁶,Glu⁹]glucagon (12); [des-Phe⁶,Glu⁹]glucagon (13); [des-Phe⁶]glucagon (14); and [des-His¹,des-Phe⁶]glucagon (15). The receptor binding potencies IC50 values are 48 (1), 126 (2), 40 (3), 19 (4), 100 (5), 48 (6), 2000 (7), 52 (8), 113 (9), 512 (10), 128 (11), 1000 (12), 2000 (13), 500 (14), and 200 nM (15). All analogues were found to be antagonists unable to activate the adenylate cyclase system even at concentrations as high as 10^-5 M except for analogues 6 and 8, which were found to be weak partial agonists/partial antagonists with maximum stimulation between 6−12%. In competitive inhibition experiments, all the analogues caused a right shift of the glucagon-stimulated adenylate cyclase dose−response curve. The pA2 values were 8.20 (1), 6.40 (2), 6.20 (3), 6.25 (4), 6.30 (5), 6.30 (7), 6.05 (8), 6.20 (9), 6.30 (10), 6.25 (11), 6.10 (12), 6.20 (13), 6.20 (14), and 6.35 (15).

Summary The present study was undertaken to determine the incidence and related risk factors for coronary heart diseases and hypertension in the rural population of Kheda district, Gujarat (India). The observations from the first five years of this ongoing project (May 1987–May 1992) are described in this paper. Out of an initial sample of 750 individuals in the age group 30–62 years, who were selected by stratified random sampling, 714 persons (males=429; females=285) were actually studied, after excluding those suffering from coronary heart diseases (CHD). Initially, all the included subjects were examined clinically and appropriate laboratory investigations were done. A detailed socioeconomic history was also obtained. Subsequently all of them were followed up and biannual clinical and laboratory investigations were performed. Cases of CHD were diagnosed according to the recommendations of the New York Heart Association. The overall five-year incidence of CHD was 25.17 per thousand persons. The incidence in males was 3 times higher than in females. More males suffered from myocardial infarction (MI), while in the females the incidence of sudden death was higher (33.3%). The average yearly mortality rate due to CHD was 2.46 per thousand persons. CHD was significantly associated with increased blood pressure (both diastolic and systolic), smoking, and family history of heart disease, and was weakly associated with body weight (p=0.06).

We have used glucagon and nine glucagon analogs to investigate the interactions of these ligands with glucagon-binding sites present on isolated canine hepatocytes. Curves reflecting the inhibition of 125I-labeled glucagon or 125I-labeled analog binding to cells by the 10 peptides spanned, overall, a 10(6)-fold range of hormone concentration, were consistent with hormone binding to two classes of binding sites in each case, and fell into two groups, one of which contained curves that were considerably more shallow than the other. Only conditions that emphasized prior binding to low affinity sites resulted in the rapid and extensive dissociation of receptor-bound ligand from isolated cells. Finally, all 10 peptides exhibited a concentration-dependent inhibition of the incorporation of [14C]fructose into hepatocyte glycogen that correlated best with dissociation constants for high affinity rather than for low affinity binding. We conclude that (a) the association of ligand with the high and low affinity glucagon-binding sites of isolated canine hepatocytes is a characteristic of analogs modified at diverse sites throughout the peptide hormone, (b) the different rates of dissociation of ligand from the two populations of binding sites most probably account for the biphasic dissociation of ligand from isolated cells and for the different affinities of the two receptor populations for ligand, and (c) the activity of glucagon and glucagon analogs to inhibit the incorporation of fructose into hepatocyte glycogen arises from the association of ligand with high affinity binding sites.

We have examined, by use of isolated canine hepatocytes and selected hormone analogs, the mechanisms by which glucagon modifies the accumulation of cellular cAMP. Low concentrations of glucagon (less than or equal to 3 nM) enhanced the accumulation of hepatocyte cAMP, whereas higher concentrations of the hormone diminished the effectiveness of lower ones. This biphasic concentration dependence was observed as well for some glucagon analogs, but not for others, and was apparent for cells incubated in the presence or absence of theophylline. Glucagon at high concentrations (greater than or equal to 10 nM) also inhibited the accumulation of cAMP induced by isoproterenol. The inhibitory effect of glucagon in both of these systems was reversed or attenuated by cell incubations involving the use of pertussis toxin (islet-activating protein) or a peptide antagonist of the glucagon-adenylyl cyclase system. We conclude that (a) glucagon, through its interaction with high and low affinity binding sites, can either stimulate or inhibit the production of hepatocyte cAMP; (b) the inhibitory action of the hormone appears to arise from interactions of ligand with a subset of these binding sites and to require structural characteristics in addition to those that determine receptor binding affinity per se; and (c) the glucagon and adrenergic systems involved in stimulating cAMP accumulation are linked, at least with regard to the negative effect induced by high concentrations of glucagon.

An electrically conductive plastic material was obtained by the polymerization of pyrrole on insulating polymeric materials and nylon cloth impregnated with the oxidant by vapour phase technique, resulting in a uniform, smooth and adherent coating of conducting polymer having a surface resistance ranging from 200 Ω/□ to 20 kΩ/□, which makes it suitable for applications as an antistatic material.

Electrically conductive processible polyaniline films have been synthesised from the electropolymerization of aniline under non-aqueous conditions. The characterization of the polymer was carried out by spectroscopic methods.