Proceedings of the American Psychological Association, Incorporated, for the year 1991: Minutes of the annual meeting of the Council of Representatives August 14 and 17, 1991, San Francisco, and February 29 March 1, 1992, Washington, DC.

These minutes act as the official record of the actions of the American Psychological Association (APA) taken during the year by both the Board of Directors and the Council of Representatives. The report contains sections on (1) meeting minutes; (2) elections, awards, and membership; (3) ethics; (4) Board of Directors; (5) Divisions and State Associations; (6) APA organization; (7) publications and communications; (8) convention affairs; (9) educational affairs; (10) professional affairs; (11) scientific affairs; (12) public interest; (13) ethnic minority affairs; (14) international affairs; (15) Central Office; (16) financial affairs; and (17) communications concerning outside organizations. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Physiological functions and regulation of K+ and Cl- channels in single smooth muscle cells

Solution- and solid-state c.d. spectra, as well as surface energetics values, were collected for a series of peptides derived from human salivary proline-rich glycoprotein (PRG). The acronyms and sequences for these peptides are as follows: PRG9-2 = NH2-G(1)-P(2)-CONH2, PRG9-3 = NH2-G(1)-P(2)-P(3)-CONH2, PRG9-4 = NH2-G(1)-P(2)-P(3)-P(4)-CONH2, PRG9-5 = NH2-G(1)-P(2)-P(3)-P(4)-H(5)-CONH2, PRG9-6 = NH2-G(1)-P(2)-P(3)-P(4)-H(5)-P(6)-CONH2, PRG9-7 = NH2-G(1)-P(2)-P(3)-P(4)-H(5)-P(6)-G(7)-CONH2, PRG9-8 = NH2-G(1)-P(2)-P(3)-P(4)-H(5)-P(6)-G(7)-K(8)-CONH2, and PRG9-9 = NH2-G(1)-P(2)-P(3)-P(4)-H(5)-P(6)-G(7)-K(8)-P(9)-CONH2. The presence of stable poly-L-proline II-like 'mini' helices in the solution state was found to be dependent on peptide chain length, pH, salt, and organic solvent type. Other conformational features such as kinks and beta-/gamma-turns were also found in the larger peptides. Solid-state peptide conformations were not necessarily related to their solution-state counterparts. Poly-L-proline II-like 'mini' helices, kinks, and beta-/gamma-turns were similarly found in the various substrate-bound PRG9 peptides. Surface energetics parameters suggested specific orientations for PRG9 peptides and their constituent acids and homopolymers.     

Amphiphilic poly(Ala)-b-poly(Sar) microspheres loaded with hydrophobic drug

Amphiphilic block polypeptides, (Ala)m(Sar)n, were synthesized. Transmission electron microscopy showed that three kinds of block polypeptides, (Ala)42(Sar)21, (Ala)34(Sar)22, and (Ala)34(Sar)27, formed spherical aggregates in water. Dynamic light scattering measurement revealed that the average diameters of (Ala)42(Sar)21 and (Ala)34(Sar)22 aggregates were in the range of 80-90 nm, whilst that of (Ala)34(Sar)27 was about 30 nm. The polypeptides in aqueous solution took a beta-sheet structure, while they took an alpha-helical conformation in trifluoroethanol. These polypeptide aggregates took up 8-anilinonaphthalene-1-sulfonate (ANS), and the capacity of the aggregates for ANS decreased in the order of (Ala)42(Sar)21 > (Ala)34(Sar)22 > (Ala)34(Sar)27. Sumithion, which is a commercial agricultural insecticide, was also taken up by the polypeptide aggregates. When increasing amounts of Sumithion were introduced, (Ala)42(Sar)21 aggregates kept their shape, but (Ala)34(Sar)27 aggregate increased in size. These different behaviors of the polypeptide aggregates were discussed in terms of different structure of aggregates.     

Proceedings of the American Psychological Association, Incorporated, for the year 1994: Minutes of the Annual Meeting of the Council of Representatives: August 11 and 14, 1994, Los Angeles, CA, and February 17–29, 1995, Washington D.C.

Reports minutes representing the official record of the actions of the American Psychological Association (APA) taken during 1994 by both the Board of Directors and the Council of Representatives. The Board held 6 official meetings, discussing issues related to the following topics: (1) minutes of previous meetings (2) elections, awards, membership, and human resources, (3) ethics, (4) the Board of Directors, (5) divisions and state and provincial associations, (6) the APA organization, (7) publications and communications, (8) convention affairs, (9) educational issues, (10) professional affairs, (11) scientific affairs, (12) public interest, (13) ethnic minority affairs, (14) international affairs, (15) the Central Office, and (16) financial affairs. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Variation in lipoprotein(a) concentrations among individuals with the same apolipoprotein (a) isoform is determined by the rate of lipoprotein(a) production

Lipoprotein(a) [Lp(a)] is an atherogenic lipoprotein which is similar in structure to, but metabolically distinct from, LDL. Factors regulating plasma concentrations of Lp(a) are poorly understood. Apo(a), the protein that distinguishes Lp(a) from LDL, is highly polymorphic, and apo(a) size is inversely correlated with plasma Lp(a) level. Even within the same apo(a) isoform class, however, plasma Lp(a) concentrations vary widely. A series of in vivo kinetic studies were performed using purified radiolabeled Lp(a) in individuals with the same apo(a) isoform but different Lp(a) levels. In a group of seven subjects with a single S4-apo(a) isoform and Lp(a) levels ranging from 1 to 13.2 mg/dl, the fractional catabolic rate (FCR) of 131I-labeled S2-Lp(a) (mean 0.328 day-1) was not correlated with the plasma Lp(a) level (r = -0.346, P = 0.45). In two S4-apo(a) subjects with a 10-fold difference in Lp(a) level, the FCR's of 125I-labeled S4-Lp(a) were very similar in both subjects and not substantially different from the FCRs of 131I-S2-Lp(a) in the same subjects. In four subjects with a single S2-apo(a) isoform and Lp(a) levels ranging from 9.4 to 91 mg/dl, Lp(a) concentration was highly correlated with Lp(a) production rate (r = 0.993, P = 0.007), but poorly correlated with Lp(a) FCR (mean 0.304 day-1). Analysis of Lp(a) kinetic parameters in all 11 subjects revealed no significant correlation of Lp(a) level with Lp(a) FCR (r = -0.53, P = 0.09) and a strong correlation with Lp(a) production rate (r = 0.99, P < 0.0001). We conclude that the substantial variation in Lp(a) levels among individuals with the same apo(a) phenotype is caused primarily by differences in Lp(a) production rate.     

Synthesis of Hexp-(1-->4)-beta-D-GlcpNAc-(1-->2)-alpha-D-Manp-(1-->O) (CH2)7 CH3 probes for exploration of the substrate specificity of glycosyltransferases: Part II, Hex = 3-O-methyl-beta-D-Gal, 3-deoxy-beta-D-Gal, 3-deoxy-3-fluoro-beta-D-Gal, 3-amino-3-deoxy-beta-D-Gal, beta-D-Gul, alpha-L-Alt, or beta-L-Gal

Seven analogues of the trisaccharide beta-D-Galp-(1-->4)-beta-D-GlcpNAc-(1-->2)-alpha-D-Manp-(1-->O)(CH 2)7CH3 have been synthesized as potential substrates for glycosyltransferases involved in the chain-termination of N-acetyllactosamine-type N-glycans. These compounds include: 3-O-methyl-beta-D-Galp-(1-->4)-beta-D-GlcpNAc-(1-->2)-alpha-D-Manp -(1-->O) (CH2)7CH3, 3-deoxy-beta-D-Galp-(1-->4)-beta-D-GlcpNAc-(1-->2)-alpha-D-Manp-(1 -->O) (CH2)7CH3, 3-deoxy-3-fluoro-beta-D-Galp-(1-->4)-beta-D-GlcpNAc-(1-->2)-alpha-D-M anp- (1-->O)(CH2)7Ch3, 3-amino-3-deoxy-beta-D-Galp-(1-->4)-beta-D-GlcpNAc-(1-->2)-alpha-D-Ma np- (1-->O)(CH2)7CH3, beta-D-Gulp-(1-->4)-beta-D-GlcpNAc-(1-->2)-alpha-D-Manp-(1-- >O)(CH2)7CH3, beta-L-Galp-(1-->4)-beta-D-GlcpNAc-(1-->2)-alpha-D-Manp-(1-->O)(CH 2)7CH3, and alpha-L-Altp-(1-->4)-beta-D-GlcpNAc-(1-->2)-alpha-D-Manp-(1- ->O) (CH2)7CH3. All trisaccharides were obtained by condensation of suitably modified glycosyl donors based on imidates or thioglycosides with the same disaccharide acceptor, octyl 3,4,6-tri-O-benzyl-2-O-(3,6-di-O-benzyl-2-deoxy-2-phthalimido-beta-D- glucopyranosyl)-alpha-D-mannopyranoside, followed by deprotection.     

Octoxynol presence in bear-bile

The presence of octoxynol from dried bear-bile was examined. Octoxynol was coextracted when glycolipids by Folch-Suzuki partition method. Octoxynol formed mixed-micelles with glycosphingolipids. The glycolipids were purified by DEAE-Sephadex A-25 column chromatography. The fractions containing mixed micelles were obtained from linear gradient solvent of 0.05M-0.5M ammonium acetate in methanol. HPLC ( Bondapak-NH(2) - linked to a Bondapak-C(18) column) chromatogram showed five peaks. Two possible structures for the fourth peak fraction were proposed as (CH(3))(3)C-CH(2)-C(CH(3))(2)-C(6)H(4)-OR and (CH(3))(3)C-C(CH(3))(2)-CH(2)-C(6)H(4)-OR by NMR spectroscopy. The structure was further confirmed by electrospray tandem mass spectrometry (ESI MS/MS). The spectrum showed a protonated molecule at m/z 559 and three different series of ions with mass difference of 44 were detected in the MS/MS spectrum. Therefore, the structure of the fourth peak fraction from HPLC was confirmed as octoxynol, (CH(3))(3)C-CH(2)-C(CH(3))(2)-C(6)H(4)-(OCH(2)-CH(2))n-OH, based on mass spectrometry and NMR spectroscopy.     

Reactivity of homocysteine-thiolactone and alpha-methylhomocysteine-thiolactone with e-(aq) and OH-radical: a pulse radiolysis study

The efficient radiation protecting agents homocysteine-thiolactone x HCl (HCTL x HCl) and its alpha-alkylated derivative (alpha-methyl-homocysteine, alpha-MHCTL x HCl) have been investigated in respect to the identification of the primarily formed species after absorption of ionizing radiation using pulse radiolysis technique.The reaction of e-(aq) with the unprotonated form of HCTL (k = 2.1 x 10(9) dm3 mol(-1) s(-1)) is leading to the formation of a radical anion having two absorption bands: at 275 nm (epsilon = 2500 dm3 mol(-1) cm(-1)) and 510 nm (epsilon = 930 dm3 mol(-1) cm(-1)), which decay with 2k = 2.3 x 10(9) dm3 mol(-1) s(-1). The protonated form of HCTL reacts with e-(aq) with k = 4.0 x 10(10) dm3 mol(-1) s(-1). The OH-radicals react with HCTL with k = 1.95 x 10(9) dm 3 mol(-1) x s(-1) resulting in a transient spectrum with lambda(max) = 265 nm (epsilon =2000 dm3 mol(-1) cm(-1)). The transients disappear with 2k = 2.1 x 10(9) dm3 mol(-1) s(-1). The reactivity of e-(aq) with alpha-MHCTL was determined for both forms: for the protonated, k = 1.25 x 10(10) dm3 mol(-1) s(-1) and for the unprotonated, k = 2.6 x 10(9) dm3 mol(-1) s(-1). The transient absorption spectrum at pH = 8.4 shows two absorption bands: lambda = 275 nm (epsilon = 3500 dm3 x mol(-1) x cm(-1)) and 490 nm (epsilon = 1160 dm3 x mol(-1) x cm(-1)). The transients disappear with 2k = 2.2 x 10(9) dm3 x mol(-1) x s(-1). The reaction of OH with alpha-MHCTL x HCl,k = 8.4 x 10(9) dm3 x mol(-1) x s(-1) (pH = 8.6) is resulting in an absorption spectrum with lambda(max) < 260 nm and an absorption band at 350 nm (epsilon = 510 dm3 x mol(-1) x cm(-1)). Up to 50 micros after pulse the transients decay with 2k = 5.5 x 10(9) dm3 x mol(-1) x s(-1) and thereafter by a k = 8.4 x 10(9) dm3 x mol(-1) x s(-1) (pH = 8.6) is resulting in an absorption spectrum with lambda(max) < 260 nm and an absorption band at 350 nm (epsilon = 510 dm3 x mol(-1) x cm(-1)). Up to 50 micros after pulse the transients decay with 2k = 5.5 x 10(9) dm3 x mol(-1) x s(-1) and thereafter by a first order reaction. In addition, the formation of some products was also studied. The yield of ammonia resulting from alpha-MHCTL x HCl strongly depends on pH, e.g. at pH = 5.1 Gi (NH3) = 0.95, whereas at pH = 9.15 it increases to Gi = 3.1. Hydrogen sulphide is formed in airfree solutions, Gi (H2S) = 0.29, whereas in the presence of N2O it is reduced to Gi (H2S) = 0.10. Some probable reaction mechanisms are presented.     

Proceedings of the American Psychological Association, Incorporated, for the legislative year 1997: Minutes of the Annual Meeting of the Council of Representatives, August 14 and 17, Chicago, Illinois; and June, August and December 1997 meetings of the Board of Directors.

Reports minutes representing the official record of the actions of the American Psychological Association (APA) taken during 1997 by both the Board of Directors and the Council of Representatives. These proceedings reflect association business conducted during the March–December 1997 legislative year. Main topical headings regarded the following topics: (1) minutes of meetings, (2) elections, awards, membership, and human resources; (3) ethics, (4) Board of Directors, (5) Divisions and State and Provincial Associations, (6) organization of APA, (7) publications and communications, (8) convention affairs, (9) educational affairs, (10) professional affairs, (11) scientific affairs, (12) public interest, (13) ethnic minority affairs, (14) international affairs, (15) central office, (16) financial affairs, and (17) communications concerning outside organizations. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Proceedings of the American Psychological Association, Incorporated, for the year 1995: Minutes of the annual meeting of the Council of Representatives: August 10 and 13, 1995, New York, NY, and February 16–18, 1996, Washington, DC.

Reports minutes representing the official record of the actions of the American Psychological Association (APA) taken during 1995 by both the Board of Directors and the Council of Representatives. Topics include (1) minutes of meetings; (2) elections, awards, membership, and human resources; (3) ethics; (4) Board of Directors; (5) divisions and state and provincial associations; (6) organization of the APA; (7) publications and communications; (8) convention affairs; (9) educational affairs; (10) professional affairs; (11) scientific affairs; (12) public interest; (13) ethnic minority affairs; (14) international affairs; (15) Central Office; (16) financial affairs; and (17) communications concerning outside organizations. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Chemistry of urinary mannosides excreted in mannosidosis

Mannose-rich oligosaccharides have been isolated from urines of 5 patients with mannosidosis. Their compositon and structure were determined. Three of them have been previously described by Norden et al: alpha p-Manp-(1 leads to 3) beta-d-Manp-(1 leads to 4) d-GlcNAcp; alpha-p-Manp-(1 leads to 2), alpha-d-Manp-(1 leads to 3) beta-d-Manp-(1 leads to 4) d-GlcNAc and alpha-d-Manp-(1 leads to 2) alpha-d-Manp-(1 leads to 2) alpha-d-Manp-(1 leads to 3) beta-d-Manp-(1 leads to 4) d-GlcNAcp, but the four others are new entities: alpha-d-Manp-(1 leads to 3) (alpha-d-Manp-(1 leads to 2) alpha-d-Manp-(1 leads to 2) alpha-d-Manp-(1 leads to 6) beta-d-Manp-(1 leads to 4) GlcNAcp; alpha-d-Manp-(1 leads to 2) alpha-d-Manp-(1 leads to 3) (alpha-d-Manp-(1 leads to 2) alpha-d-Manp-(1 leads to 6) beta-d-Manp-(1 leads to 4) GlcNAcp; alpha-d-Manp-(1 leads to 2), alpha-d-Man-(1 leads to 3) (alpha-d-Manp-(1 leads to 6) beta-d-Manp-(1 leads to 4) GlcNAp and alpha-d-Manp-(1 leads to 2) alpha-d-Manp-(1 leads to 3) (alpha-d-Manp-(1 leads to 6) beta-d-Manp-(1 leads to 4) GlcNAcp. These structures are related to the glycans of "oligomannosidic type" present in numerous glycoproteins. All possess a N-acetylglucosamine residue in terminal reducing position and reinforce the hypothesis of Kobata et al. and Montreuil et al. that catabolism of glycans N-glucosidically linked to the protein moiety begins by the aciton of a beta-endo-N-acetylglucosaminidase.     

Microbiological transformation of manoyl oxide derivatives by Mucor plumbeus

Biotransformations of jhanol (18-hydroxymanoyl oxide) (2), jhanidiol (1beta,18-dihydroxymanoyl oxide) (3), and 1-oxo-jhanol (1-oxo-18-hydroxymanoyl oxide) (4) by the fungus Mucor plumbeus have been studied. In the incubation of 2 there exists a preference for hydroxylation at C-2(alpha) (8) and C-6(beta) (9-11) and, to a lesser degree, at C-1(alpha) (7), C-11(alpha) (6), and C-11(beta) (5 and 10). In the second substrate (3), the presence of a 1beta-hydroxyl group inhibits 6beta- or 11-hydroxylation. Epoxidation of the vinyl group constitutes the main reaction, with the positions 2alpha (14) and 3beta (15) being hydroxylated. In the incubation of 4, there was a preference for 6beta-hydroxylation (21) or epoxidation of the vinyl group (22). Other hydroxylations observed were at the 2alpha (19), 2beta (20), 3alpha (23), 3beta (24), and 11beta (18) positions.     

Relationships of age and seniority with career variables of engineers and scientists.

Studied changing career experiences of professional engineers and scientists in 1967 (n = 290) and 1969 (n = 90). Both age and seniority were related to (a) amount of various needs, (b) aspirations for needs, (c) importance of needs, (d) satisfaction with needs, (e) self-image, (f) organizational climate, (g) job challenge, (h) job involvement, (i) intrinsic motivation, (j) perceived performance, and (k) perceived effort. Ss completed objective measures of these variables, including the Porter Need Satisfaction Questionnaire. On the basis of these correlations, 1-way analyses of variance between each variable and the different age groups, and rank orders for different age groups, it is concluded that career stages (early, middle, and late) did exist with different variables characterizing different stages. (26 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Aspects of health education connected with the process of preparing for old age (author''s transl)]

Bilirubin kinetics were studied in an isolated, perfused rat liver system using unconjugated (14C) bilirubin (UC(14C)B) and delta-amino (4-14 C) levulinic acid (A(14 C)LA) to derive a suitable compartmental model. Plasma disappearance of UC(14C)B, plasma appearance of conjugated (14c) bilirubin (C(14C)B) and biliary excretion of C(14C)B were followed for 90-120 min following injection of UC(14C)B. Hepatic content of labeled bilirubin 12 min after the injection of UC(14C)B was determined directly in five separate perfusion experiments. UCB was found to reflux back to plasma from liver in two experiments using A(14C)LA. Bilirubin binding to red blood cells (6-8% of the perfusate level) and the components of the perfusion apparatus (4-6% of perfusate level) was estimated by performing a control experiment without the liver. A six compartment model was necessary and adequate to explain the experimental data and current knowledge of bilirubin metabolism: (1) UCB bound to red blood cells and the perfusion apparatus, (2) plasma UCB, (3) liver UCB, (4) liver CB, (5) plasma CB, and (6) bile CB. The proposed model could serve as a reference point for studies of bilirubin kinetics in whole animals for normal and abnormal states.     

Proceedings of the American Psychological Association, Incorporated, for the year 1984: Minutes of the annual meeting of the Council of Representatives August 23 and 26, 1984, Toronto, Ontario, Canada and February 1–3, 1985, Washington, D.C.

These minutes constitute the official record of actions of the Association taken during the year, by both the Board of Directors and the Council of Representatives. Included are (I) Minutes of Meetings in 1984-1985, (II) Elections, Awards, Membership, and Human Resources, (III) Ethics, (IV) Board of Directors, (V) Divisions and State Associations, (VI) Organization of the APA, (VII) Publications and Communications, (VIII) Convention Affairs, (IX) Educational Affairs, (X) Professional Affairs, (XI) Scientific Affairs, (XII) Social and Ethical Responsibility for Psychology, (XIII) Ethnic Minority Affairs, (XIV) International Affairs, (XV) Central Office, (XVI) Financial Affairs, and (XVII) Communications Concerning Outside Organizations. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Incidence of spontaneous subarachnoid hemorrhage among Hispanics and non-Hispanic whites in New Mexico

Tri(gamma-glutamylcysteinylglycinyl)trithioarsenite (AsIII(GS)3) is formed in cells and is a more potent mixed-type inhibitor of the reduction of glutathione disulfide (GSSG) by yeast glutathione (GSH) reductase than either arsenite (AsIII) or GSH. The present work examines the effects of valence and complexation of arsenicals with GSH or L-cysteine (Cys) upon potency as competitive inhibitors of the reduction of GSH disulfide (GSSG) by yeast GSH reductase. Trivalent arsenicals were more potent inhibitors than their pentavalent analogs, and methylated trivalent arsenicals were more potent inhibitors than was inorganic trivalent As. Complexation of either inorganic trivalent As or methylarsonous diiodide (CH3As(III)I2) with Cys or GSH produced inhibitors of GSH reductase that were severalfold more potent than the parent arsenicals. In contrast, dimethylarsinous iodide ((CH3)2As(III)I) was a more potent inhibitor than its complexes with either GSH or Cys. Complexes of CH3AsIII with GSH (CH3-AsIII(GS)2) or with Cys (CH3AsIII(Cys)2) were the most potent inhibitors, with Ki's of 0.009 and 0.018 mM, respectively. Inhibition of GSH reductase by arsenicals or arsenothiols was prevented by addition of meso-2,3-dimercaptosuccinic acid (DMSA) to a mixture of enzyme, GSSG, and inhibitor before addition of NADPH. DMSA added to the reaction mixture after NADPH reversed inhibition by (CH3)2As(III)I but had little effect on inhibition by CH3As(III)I2, Ch3AsIII(GS)2, CH3AsIII(Cys)2, or AsIII(GS)3. Partial redox inactivation of the enzyme with NADPH increased the inhibitory potency of CH3As(III)I2 and (CH3)2As(III)I and changed the mode of inhibition for CH3As(III)I2 from competitive to noncompetitive. The greater potency of methylated trivalent arsenicals and arsenothiols than of inorganic trivalent As suggests that biomethylation of As could yield species that inhibit reduction of GSSG and alter the redox status of cells.     

Perturbations Involving nu1 of NCCN

From high-resolution infrared spectra of 14N12C12C14N, 14N13C13C14N, and 15N12C12C15N, we find that the levels 1000(0)0(0), 1000(0)1(1), 1000(0)2(0,2), and 1000(0)3(1,3) have very pronounced perturbations. Our analysis shows that these perturbations are due to a vibrational resonance among the levels 1000(0)0(0), 0102(0)2(0), and 0102(0)2(2) in the one case, and equivalent levels with one or more additional quanta of nu5 in the other three cases. The resonance constant for the perturbation involving nu1 is 0.25 cm-1. It has the dependence on v5 and l5 that is expected for the sextic potential constant, K124455, although it seems too large for such a high-order constant. The Deltal (or Deltak) = 2 interaction between, for instance, 1000(0)0(0) and 0102(0)2(2e) is shown to be primarily due to the l-type resonance mixing of the 0102(0)2(0) and 0102(0)2(2e) states. The resonance is nearly "turned off" for the 1000(0)2(0,2) and 1000(0)3(1,3) states of 14N13C13C14N because there are no level crossings between the interacting states and the band centers are too far away to have an obvious effect, although careful analysis shows that the perturbation can be seen in their effective centrifugal distortion constants. The spectrum of 15N12C12C15N shows level crossings only in the case of the 1000(0)1(1), 1000(0)2(0,2), and 1000(0)3(1,3) states. Copyright 1999 Academic Press.     

Generation of chromophore Tyr-containing mutants of the ribosomal protein L7/L12 from Escherichia coli by site-directed mutagenesis and characterization

1. The effects of tachykinins and capsaicin were studied by means of intracellular membrane potential and isometric tension recordings in the isolated trachea of the guinea-pig. 2. The basal membrane potential averaged -51 mV, and most preparations demonstrated spontaneous slow waves. Tetraethylammonium (TEA), a potassium channel blocker (8 x 10(-3) M), depolarized the membrane potential to -44 mV and induced a rhythmic activity. 3. In control solution, substance P (10(-8)-10(-6) M), [Nle10]-neurokinin A(4-10) (10(-8)-10(-6) M) and capsaicin (10(-7)-10(-6) M) induced concentration-dependent depolarizations which were statistically significant at the highest concentration tested (depolarization by 10(-6) M: 8, 11 and 16 mV for the NK1 agonist, the NK2 agonist and capsaicin, respectively). 4. In the presence of TEA (8 x 10(-3) M), the three substances induced depolarizations which were statistically significant at the highest concentration tested for substance P (10(-6) M) and at 10(-7) and 10(-6) M for both [Nle10]-neurokinin A(4-10) and capsaicin (depolarization by 10(-6) M: 11, 17 and 10 mV for substance P, [Nle10]neurokinin A(4-10) and capsaicin, respectively). 5. In the presence or absence of tetraethylammonium, [MePhe7]-neurokinin B (10(-8)-10(-6) M) did not induce any significant changes in membrane potential. 6. The depolarizing effects of substance P (10(-6) M) and [Nle10]-neurokinin A(4-10) (10(-6) M) were blocked only by the specific antagonists for NK1 and NK2 receptors, SR 140333 (10(-7) M) and SR 48968 (10(-7) M), respectively. The effects of capsaicin (10(-6) M) were partially inhibited by each antagonist and fully blocked by their combination. 7. Substance P (10(-9) to 10(-4) M), [Nle10]-neurokinin A(4-10) (10(-10) to 10(-5) M), [MePhe7]-neurokinin B and capsaicin (10(-7) to 10(-5) M) evoked concentration-dependent contractions. 8. The contractions to substance P were significantly inhibited by SR 140333 (10(-8) to 10(-6) M) but unaffected by SR 48968 (10(-8) to 10(-6) M). Furthermore, the response to [Nle10]-neurokinin A(4-10) was significantly inhibited by SR 48968 and unaffected by SR 140333 at the same concentrations. Although SR 48968 (10(-7) M) alone did not influence the effects of substance P, it potentiated the inhibitory effect of SR 140333 (10(-7) M). A similar synergetic effect of these two compounds was observed in the inhibition of the contractile response to [Nle10]-neurokinin A(4-10). 9. Neither SR 140333 (10(-7) M) nor SR 48968 (10(-7) M) alone influenced the contractions to [MePhe7]-neurokinin B and capsaicin. However, the combination of the two antagonists abolished the contractions to either peptide. 10. These results demonstrate that the stimulation of both NK1 and NK2 tachykinin-receptors induced contraction and depolarization of the guinea-pig tracheal smooth muscle and that both receptors were stimulated during the endogenous release of tachykinins by capsaicin. There was no evidence for a major role of NK3 receptors in the contractile and electrical activity of the guinea-pig isolated trachea.     

Excitatory amino acid receptor antagonists: resolution, absolute stereochemistry, and pharmacology of (S)- and (R)-2-amino-2-(5-tert-butyl-3-hydroxyisoxazol-4-yl)acetic acid (ATAA)

We have previously shown that (RS)-2-amino-2-(5-tert-butyl-3-hydroxyisoxazol-4-yl)acetic acid (ATAA) is an antagonist at N-methyl-D-aspartic acid (NMDA) and (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors. We have now resolved ATAA via diastereomeric salt formation using N-BOC protected ATAA and (R)- and (S)-phenylethylamine. Enantiomeric purities (ee > 98%) of (R)- and (S)-ATAA were determined using the Crownpak CR(-) and CR(+) columns, respectively. The absolute configuration of (R)-ATAA was established by an X-ray crystallographic analysis of the (R)-phenylethylamine salt of N-BOC-(R)-ATAA. Like ATAA, neither (R)- nor (S)-ATAA significantly affected (IC50 > 100 microM) the receptor binding of tritiated AMPA, kainic acid, or (RS)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid, the latter being a competitive NMDA antagonist. Electrophysiological experiments, using the rat cortical wedge preparation, showed the NMDA antagonist effect as well as the AMPA antagonist effect of ATAA to reside exclusively in the (R)-enantiomer (Ki = 75 +/- 5 microM and 57 +/- 1 microM, respectively). Neither (R)- nor (S)-ATAA significantly reduced kainic acid-induced excitation (Ki > 1,000 microM).