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1.
To investigate receptor selectivity and possible species selectivity of a number of NPY analogues and fragments, receptor binding studies were performed using cell lines and membranes of several species. NPY displays 4–25-fold higher affinity for the Y 2 receptor than for the Y 1 receptor. The affinity of [Leu 31,Pro 34]NPY is 7–60-fold higher for the Y 1 receptor when compared with the Y 2 subtype. Species selectivity within the Y 2 receptors is demonstrated by PYY(3–36), NPY(2–36), NPY(22–36), and NPY(26–36). It is shown that NPY(22–36) is species selective for the human Y 2 subtype ( Ki of 0.3 n M) compared with the rabbit and rat Y 2 receptor ( Ki of 2 and 10 n M, respectively). PYY(3–36) displays highest affinity for the human and rabbit Y 2 subtype ( Ki of 0.03 and 0.17 n M). The screening of NPY analogues and fragments revealed that highest affinity for the human Y 2 receptor is shown by NPY(2–36) and PYY(3–36). In addition, PYY(3–36) and NPY(2–36) are not only subtype selective, but also species selective. 相似文献
2.
Neurotransmitters and neuropeptides play important roles in the regulation of various neuroendocrine functions particularly feeding. The aim of this study was to investigate whether a functional interaction occurs among neuropeptide Y (NPY) at NPY Y 1 receptors and noradrenaline overflow, as this may contribute to the regulation of appetite. The release of endogenous noradrenaline and its metabolite 3,4-dihydroxyphenylglycol (DHPG) were examined from hypothalamic and medullary prisms using the technique of in vitro superfusion and high performance liquid chromatography (HPLC) with coulometric detection. Noradrenaline and DHPG overflow was investigated at rest, in response to NPY (0.1 μM) and in response to the NPY Y 1 receptor agonist, [Leu 31,Pro 34]NPY (0.1 μM). Perfusion with NPY and [Leu 31,Pro 34]NPY significantly reduced noradrenaline overflow from the hypothalamus and medulla. Perfusion with NPY and [Leu 31,Pro 34]NPY was without significant effect on hypothalamic DHPG overflow, while medullary DHPG overflow was significantly reduced by NPY and [Leu 31,Pro 34]NPY. Results from this study provide evidence of NPY Y 1 receptor-mediated inhibition of noradrenaline release in the hypothalamus and medulla, further illustrating a complex interaction between neurotransmitters and neuropeptides within the rat brain. 相似文献
3.
To differentiate NPY receptor subtypes, Y 1 and Y 2, in terms of their impact on feeding behavior, the intact molecule NPY(1–36) and the 3 fragments, NPY(2–36), the Y 1 agonist [Leu 31,Pro 34]NPY, and the Y 2 agonist NPY(13–36), were injected (100 pmol/0.3 μl) into the hypothalamic paraventricular nucleus (PVN) of freely feeding rats. A computer-automated data acquisition system was employed in these experiments to permit a detailed analysis of feeding over the 12-h nocturnal cycle, in animals maintained on pure macronutrient diets. The results demonstrate that: 1) NPY(1–36) potentiates feeding behavior, primarily carbohydrate ingestion, by increasing the size and duration of the first meal after injection, rather than by affecting meal number or feeding rate, suggesting that NPY acts through mechanisms of satiety. The potentiation of carbohydrate intake occurs in association with a suppression of protein intake, which is strongest during the second meal after injection and which further increases the proportion of carbohydrate in the diet. No changes in fat ingestion are seen. 2) NPY(2–36), with the N-terminal tyrosine residue deleted, is equally potent to NPY(1–36) in potentiating carbohydrate intake and increasing meal size; however, it is less selective than NPY(1–36), producing an additional, smaller increase in consumption of protein. 3) The stimulatory effect of these peptides on carbohydrate intake and meal size is similarly observed, with somewhat reduced potency, after PVN injection of the selective Y 1 agonist [Leu 31,Pro 34]NPY which, like NPY(1–36), also reduces protein intake. 4) The Y 2 receptor agonist, NPY(13–36), causes a decrease in the ingestion of carbohydrate, a smaller decline in protein intake, and a reduction in meal size. It is proposed that hypothalamic Y 1 receptors mediate the stimulatory effect of NPY on carbohydrate intake and meal size, while Y 2 receptors have the opposite effect of suppressing carbohydrate intake, possibly by altering presynaptic release of monoamines known to influence nutrient ingestion. 相似文献
4.
To study structure-activity relationships of growth hormone-releasing hormone (GHRH), a competitive binding assay was developed using cloned porcine adenopituitary GHRH receptors expressed in human kidney 293 cells. Specific binding of [His 1, 125I-Tyr 10,Nle 27]hGHRH(1–32)-NH 2 increased linearly with protein concentration (10–45 μg protein/tube). Binding reached equilibrium after 90 min at 30°C and remained constant for at least 240 min. Binding was reversible to one class of high-affinity sites ( Kd = 1.04 ± 0.19 n M, Bmax = 3.9 ± 0.53 pmol/mg protein). Binding was selective with a rank order of affinity (IC 50) for porcine GHRH (2.8 ± 0.51 n M), rat GHRH (3.1 ± 0.69 n M), [ N-Ac-Tyr 1,
-Arg 2]hGHRH(3–29)-NH 2 (3.9 ± 0.58 n M), and [
-Thr 7]GHRH(1–29)-NH 2 (189.7 ± 14.3 n M), consistent with their binding to a GHRH receptor. Nonhydrolyzable guanine nucleotides inhibited binding. These data describe a selective and reliable method for a competitive GHRH binding assay that for the first time utilizes rapid filtration to terminate the binding assay. 相似文献
5.
Since the sympathetic nervous system has been shown to exert a trophic influence on vascular smooth muscle cells (SMC), we studied the growth regulating effects of neuropeptide Y (NPY) in cooperation with the sympathetic co-transmitters noradrenaline and adenosine triphosphate (ATP) in human vascular SMC. NPY stimulated DNA synthesis in human SMC grown from subcutaneous arteries and veins (diameter: 0.4 mm) measured by [ 3H]thymidine incorporation. Also cell number and protein synthesis were stimulated. The effect was mediated through the Y 1-receptor and not Y 2 or Y 3 since the Y 1-selective NPY analogue Pro 34-NPY and peptide YY stimulated mitogenesis in the same magnitude as NPY while the NPY-fragment NPY 13–36 only had minor effects. The effect was blocked by pretreating the cells with pertussis toxin indicating a G 1/o-coupled effect. The other sympathetic co-transmitters, noradrenaline and ATP, also stimulated mitogenesis in the human SMC in a similar magnitude as NPY. When added together NPY and noradrenaline potentiated each other in the mitogenic response. ATP had mainly additive effects. This is the first demonstration that NPY, noradrenaline and ATP stimulates growth in human vascular SMC. This suggests a role of the sympathetic co-transmitters in modulating vascular tone, but also by inducing hypertrophy/hyperplasia with possible clinical consequences. 相似文献
6.
We produced and characterized three anti- C-flanking peptides of neuropeptide Y (CPON) monoclonal antibodies. The Ka for these antibodies ranged from 0.4 to 0.8 × 10 8 l/mol with an IC 50 for CPON(1–30) at about 20 n M as determined by ELISA. All these antibodies are IgG1 and recognize the 16–30 part of CPON. These antibodies and a specific anti-NPY monoclonal antibody were used to study the localization of CPON and NPY in the human kidney. The avidin-biotin technique was employed. NPY and CPON immunoreactivities were present in large amount in the renal tubules of the human kidney but not in the glomeruli. No labeling was found within the renal arterioles and veins, but some immunoreactivity was evidenced in the perivascular area. Because no specific receptor for CPON has been described to date, the presence of this peptide in the tubules may be due to a tubular reabsorption or perhaps to a local synthesis of pro-NPY. 相似文献
7.
A three-dimensional model of the human neuropeptide Y(NPY)Y 1 receptor (hY 1) was constructed, energy refined and used to simulate molecular receptor interactions of the peptide ligands NPY, [L31, P34]NPY, peptide YY (PYY) and pancreatic polypeptide (PP), and of the nonpeptide antagonist R- N2-(diphenylacetyl)- N-(4-hydroxyphenyl)methyl-argininamide (BIBP3226) and its S-enantiomer BIBP3435. The best complementarity in charges between the receptor and the peptides, and the best structural accordance with experimental studies, was obtained with amino acid 1–4 of the peptides interacting with Asp194, Asp200, Gln201, Phe202 and Trp288 in the receptor. Arg33 and Arg35 of the peptides formed salt bridges with Asp104 and Asp287, respectively, while Tyr36 interacted in a binding pocket formed by Phe41, Thr42, Tyr100, Asn297, His298 and Phe302. Calculated electrostatic potentials around NPY and hY 1 molecules indicated that ligand binding is initiated by electrostatic interactions between a highly positive region in the N- and C-terminal parts of the peptides, and a negative region in the extracellular receptor domains. Molecular dynamics simulations of NPY and BIBP3226 interactions with the receptor indicated rigid body motions of TMH5 and TMH6 upon NPY binding as mechanisms of receptor activation, and that BIBP3226 may act as an antagonist by constraining these motions. 相似文献
8.
The interaction of the novel CCK analogs JMV-180, JMV-320, and JMV-332 with CCK-B/gastrin receptors on small cell lung cancer (SCLC) cells was investigated. JMV-180, JMV-320, and JMV-332 potently inhibited specific binding of 125I-CCK-8 to CCK-B/gastrin receptors expressed on the SCLC cell line NCI-H345 (H345) with IC 50 values of 4.9, 1.8, and 7.0 n M, respectively. JMV-320 and JMV-332 stimulated intracellular calcium ([Ca 2+] i) release in a dose-dependent manner in cells preloaded with indo-1. JMV-180 did not stimulate [Ca 2+] i but inhibited the [Ca 2+] i release elicited by 10 n M CCK-8 in a dose-dependent manner. These data indicate that JMV-320 and JMV-332 function as CCK-B/gastrin receptor agonists while JMV-180 functions as a CCK-B/gastrin receptor antagonist in H345 cells. 相似文献
9.
R. LEMA-KISOKA, N. HAYEZ, I. LANGER, P. ROBBERECHT, E. SARIBAN AND C. DELPORTE. Characterization of functional VIP/PACAP receptors in the human erythroleukemic HEL cell line. PEPTIDES. The presence of VIP/PACAP receptors was investigated on the human erythroleukemic cell line HEL. Specific binding of [ 125I]-PACAP or [ 125I]-VIP on HEL cells or membranes was very low and did not allow to perform competition curves. At 37°C PACAP transiently increased cAMP levels in the presence of the non-specific phosphodiesterase inhibitor IBMX, suggesting rapid desensitization. Kinetic studies revealed that optimal conditions to measure the EC 50 of PACAP(1–27) were 10 min at 20°C. Under those conditions, PACAP-related peptides increased cAMP levels with EC 50 in agreement with the pharmacological profile of the VPAC 1 receptor subtype: PACAP = VIP > [K 15, R 16, L 27]VIP(1–7)/GRF(8–27) = [R 16]ChSn (two VPAC 1 agonists) HELODERMIN = secretin. RO 25–1553, a selective activator of VPAC 2 receptor was inactive at 1 μM. Dose-response curves of VPAC 1 agonist molecules (PACAP, VIP, [K 15, R 16, L 27]VIP(1–7)/GRF(8–27), [R 16]ChSn) were shifted to the right by the VPAC 1 receptor antagonist [AcHis 1, D-Phe 2, Lys 15, Leu 17]VIP(3–7)/GRF(8–27), with a K i of 3 ± 1 nM ( n = 3). The presence of VPAC 1 receptor mRNA was confirmed by RT-PCR. Preincubation with PACAP or PMA showed that VPAC 1 receptors underwent homologous and heterologous desensitization. This study provides the first evidence for the expression of functional VPAC1 receptors undergoing rapid desensitization in HEL cells. 相似文献
10.
Experiments were performed to relate receptor binding to biologic activity for the contractile effect of neurotensin (NT) in guinea pig ileum. The contractile response was examined on pieces of ileum under 1 g tension in a 5 ml bath of oxygenated Tyrode's at 38°C. NT contracted the longitudinal muscle (ED 50, 0.3 n M), the 2–3 g response peaking at 1 min and fading rapidly. In the presence of atropine (1 μ M), ≥50% of the response was blocked and the residual effect gave an ED 50 of 1.4 n M. In the presence of atropine and CP-96,345, a substance P receptor antagonist (0.2 μ M), no contraction was observed at 20 n M NT. Thus, there were two components to the response, one involving acetylcholine (ED 50, 0.3 n M) and one substance P (ED 50, 1.4 n M). Using membrane preparations and 125I-labeled NT, specific, high affinty receptors for NT were demonstrated in the muscle and myenteric plexus. Scatchard analyses indicated the presence of two binding sites ( Kds: 0.1 n M and 2 n M). Sodiu ion and GTP analogs inhibited binding. Binding and biologic activity were similar in regard to dependence on specific groups within NT and sensitivity to metal ions. The high potency of Hg ++ was consistent with an involvement of free sulfhydryl group(s) in the binding reaction; this was supported by work with SH-directed agents. The results suggest that two receptor types or configurations may mediate the two components of the contractile effect of NT on guinea pig ileum. 相似文献
11.
Parathyroid hormone (PTH) has been shown to have actions within the brain, suggesting the presence of central PTH receptors. This possibility was examined by determining the binding of 125I-labeled [Nle 8,18,Tyr 34]bovine PTH to the plasma membranes of rat and rabbit brains. Specific binding of the tracer to membranes of the whole brain was time and tissue dependent, and was greater with membranes from the hypothalamus than with membranes from the cerebellum, cerebrum, or brain stem. The binding of the tracer to rat hypothalamic membranes was saturable and competitively displaced by unlabeled PTH(1–34), PTH(3–34), [Nle 8,18,Tyr 34]PTH(1–34), and by PTH-related protein, indicating the presence of a single class of high-affinity (dissociation constant = 2–5 n M), low-capacity (maximum binding capacity, Bmax = 110–250 fmol/mg protein) binding site. The binding of radiolabeled PTH to these sites was not displaced by unrelated peptides of comparable molecular size (calcitonin, calcitonin-gene related peptide, adrenocorticotropin). The binding of PTH to these sites did not, however, appear to stimulate adenylate cyclase activity, as in peripheral PTH target sites. Thus, although these results indicate the presence of PTH receptors in the brain, these binding sites have a lower affinity than those in peripheral tissues and may utilize a different signal transduction system. 相似文献
12.
Guide cannula were implanted in rats aimed at the paraventricular nucleus (PVN) of the hypothalamus for microinjection of neuropeptide Y (NPY), D-NPY 27–36, or vehicle. In the Wistar rat, there was no significant effect on the consumption of ethanol. In Myers’ high ethanol preferring (mHEP) rats, D-NPY 27–36 caused a significant 54% decrease in ethanol consumption from baseline, but the response was not different from vehicle. NPY-induced feeding in satiated Wistar rats, was blocked by a Y 1 receptor antagonist, D-NPY 27–36. D-NPY 27–36 decreased 78% feeding in food-deprived rats. Thus, neither the Wistar nor the mHEP rat perceives ethanol as a source of calories comparable to food. 相似文献
13.
Recent studies from our laboratory resolved two subtypes of the κ 2 binding site, termed κ 2a and κ 2b, using guinea pig, rat, and human brain membranes depleted of μ and δ receptors by pretreatment with the site-directed acylating agents BIT (μ-selective) and FIT (δ-selective). 6β-Iodo-3,14-dihydroxy-17-cyclopropylmethyl-4,5-epoxymorphinan (IOXY), an opioid antagonist that has high affinity for κ 2 sites, was radioiodinated to maximum specific activity (2200 Ci/mmol) and purified by high pressure liquid chromotography and used to characterize multiple κ 2 binding sites. The results indicated that [ 125I]IOXY, like [ 3H]bremazocine, selectively labels κ 2 binding sites in rat brain membranes pretreated with BIT and FIT. Using 100 n M [
-Ala 2-MePhe 4,Gly-ol 5]enkephalin to block [ 125I]IOXY binding to the κ 2b site, two subtypes of the κ 2a binding site were resolved, both in the absence and presence of 50 μ M 5′-guanylyimidodiphosphate. Viewed collectively, these results provide further evidence for heterogeneity of the κ opioid receptor, which may provide new targets for drug design, synthesis, and therapeutics. 相似文献
14.
The action of rotameric probes introduced either in position 7 or 8 in the sequence of substance P (SP) was investigated, i.e.
-tetrahydroisoquinoleic acid (Tic),
-fluorenylglycine (Flg),
-diphenylalanine (Dip), the diastereoisomers of
-1-indanylglycine (Ing) and
-benz[ƒ]indanylglycine (Bfi), the Z- and E-isomers of dehydrophenylalanine and dehydronaphthylalanine (Δ ZPhe, Δ EPhe, Δ ZNal, Δ ENal) and
(Dmp). The aim of this study was the topographical characterization of the binding subsites of human NK-1 receptor expressed in CHO cells, especially the S 7 and S 8 subsites, corresponding to residues Phe 7 and Phe 8 of substance P. According to the binding potencies of these substituted-SP analogues, the S 7 binding subsite is smaller than the S 8 subsite: the S 7 subsite accepts only one aromatic nucleus, while the S 8 can accommodate three coplanar nuclei altogether. These findings are compatible with the idea that the S 8 binding subsite may reside in the extracellular loops of the hNK-1 receptor. NK-1 agonists bind to human NK-1 receptor and activate the production of both inositol phosphates and cyclic AMP. As already quoted for septide, [pGlu 6, Pro 9]SP(6–11), discrepancies are observed between affinity ( Ki) and activity (EC 50) values for IPs production. While a weak correlation between Ki and EC 50 values for IPs production could be found ( r = 0.70), an excellent correlation could be demonstrated between their affinities ( Ki) and their potencies (EC 50) for cAMP production ( r = 0.97). The high potency (EC 50) observed for ‘septide-like’ molecules on PI hydrolysis, compared to their affinity is not an artefact related to the high level of NK-1 receptors expressed on CHO cells since a good correlation was found between EC 50 values obtained for PI hydrolysis and those measured for spasmogenic activity in guinea pig ileum bioassay ( r = 0.94). According to the binding potencies of constrained analogues of phenylalanine, the S7 binding subsite of human NK-1 receptor is small, whereas the S8, which can accommodate three coplanar nuclei, might probably reside in the extracellular loop. The discrepancies observed between affinity (Ki) and activity (EC50) values for IPs production are not an artefact of CHO cells since a good correlation was found between EC50 for PI hydrolysis and those measured in guinea pig ileum bioassay. 相似文献
15.
Bhargava, H. N., V. M. Villar, J. Cortijo and E. J. Morcillo. Binding of [ 3H][D-Ala 2, MePhe 4, Gly-ol 5]enkephalin, [ 3H][D-Pen 2, D-Pen 5]enkephalin, and [ 3H]U-69,593 to airway and pulmonary tissues of normal and sensitized rats. Peptides 18(10) 1603–1608, 1997.—The role of endogenous opioid peptides in the regulation of bronchomotor tone, as well as in the pathophysiology of asthma is uncertain. We have studied the binding of highly selective [ 3H]labeled ligands of μ-([D-Ala 2, MePhe 4, Gly-ol 5]enkephalin; DAMGO), δ ([D-Pen 2, D-Pen 5]enkephalin; DPDPE), and κ-(U-69,593) opioid receptors to membranes of trachea, main bronchus, lung parenchyma and pulmonary artery obtained from normal (unsensitized) and actively IgE-sensitized rats acutely challenged with the specific antigen. [ 3H]DAMGO, [ 3H]DPDPE and [ 3H]U-69,593 bound to membranes of normal and sensitized tissues at a saturable, single high-affinity site. The rank order of receptor densities in normal tissues was δ- ≥ κ- ≥ μ-, with lung parenchyma exhibiting the greatest binding capacity for δ- and μ- receptors compared to the other regions examined. The Kd values showed small differences between ligands and regions tested. The μ- and δ-opioid receptor densities were decreased in sensitized main bronchus and lung parenchyma, respectively, compared to normal tissues. By contrast, κ-opioid receptor density was augmented in sensitized lung parenchyma but an increase in Kd values was also observed. These differential changes in the density and affinity of opioid receptor types may be related to alterations in endogenous opioid peptides during the process of sensitization. 相似文献
16.
The mechanisms by which neurotensin (NT) was inactivated by differentiated neuroblastoma and HT29 cells were characterized. In both cell lines, the sites of primary cleavages of NT were Pro 7-Arg 8, Arg 8-Arg 9 and Pro 10-Tyr 11 bonds. The cleavage at the Pro 7-Arg 8 bond was totally inhibited by N-benzyloxycarbonyl-Prolyl-Prolinal and therefore resulted from the action of proline endopeptidase. This peptidase also contributed in a major way to the cleavage at the Pro 10-Tyr 11 bond. However the latter breakdown was partly due to an NT-degrading neutral metallopeptidase. Finally, we demonstrated the involvement of a recently purified rat brain soluble metalloendopeptidase at the Arg 8-Arg 9 site by the use of its specific inhibitor N-[1(R,S)-carboxy-2-Phenylethyl]-alanylalanylphenylalanine-p-aminobenzoate. The secondary processing of NT degradation products revealed differences between HT29 and N1E115 cells. Angiotensin converting enzyme was shown to degrade NT 1–10 and NT 1–7 in N1E115 cells but was not detected in HT29 cells. A post-proline dipeptidyl aminopeptidase activity converted NT 9–13 into NT 11–13 in HT29 cells but not in N1E115 cells. Finally bestatin-sensitive aminopeptidases rapidly broke down NT 11–13 to Tyr in both cell lines. Models for the inactivation of NT in HT29 and N1E115 cells are proposed and compared to that previously described for purified rat brain synaptic membranes. 相似文献
17.
PF4 has previously been shown to have potent inhibitory effects on myoactivity of somatic muscle strips from the nematode, Ascaris suum. This study examined the bioactivity and metabolic stability of position 2- and position 5-modified analogues of PF4. Although the analogues [Leu 5]PF4, [Ala 2]PF4, [Gly 2]PF4, [Ala 2,Leu 5]PF4, and [Gly 2,Leu 5]PF4 all had qualitatively similar inhibitory effects on A. suum somatic muscle strips, their effects were quantitatively distinguishable and had the order of potency: PF4 = [Leu 5]PF4 [Al 2]PF4 = [Ala 2,Leu 5]PF4 [Gly 2]PF4 = [Gly 2,Leu 5]PF4. Leu 5 for Ile 5 substitutions in PF4 did not alter the activity of this peptide; however, Gly 2/Ala 2 for Pro 2 substitutions reduced, bud did not abolish, peptide activity. Peptide stability studies revealed that [Gly 2]PF4(2–7) and -(3–7) and [Ala 2]PF4(2–7), -(3–7), and -(4–7) fragments were generated following exposure to A. suum somatic muscle strips. However, the parent peptide (PF4) was not metabolized and appeared to be resistant to the sequential cleavages of native aminopeptidases. Observed analogue metabolism appeared to be due to the activity of released aminopeptidases as identical fragments were generated by incubation in medium that had been exposed to somatic muscle strips and from which the strips had been removed prior to peptide addition. It was found that the muscle stretching and bath mixing characteristics of the tension assay led to more effective release of soluble enzymes from muscle strips and thus greater peptide degradation. These studies reveal that Pro 2 in PF4 is not essential for the biological activity of this peptide; however, it does render the peptide resistant to the actions of native nematode aminopeptidases. 相似文献
18.
Biological properties of amino-terminal PTHrP analogues modified in the region 11–13 were examined using ROS 17/2.8 cells. [Leu 11,D-Trp 12,Arg 13,Tyr 36]PTHrP(1–36)amide had a 17-fold lower binding affinity for the receptor (apparent K d: 5 × 10 −8 M) than [Tyr 36]PTHrP(1–36)amide or [Arg 11,13,Tyr 36]PTHrP(1–36)amide (apparent K d for both: 2 × 10 −9 M). Moreover, it is only a weak partial agonist despite completely inhibiting radioligand binding. [Leu 11,D-Trp 12,Arg 13,Tyr 36,Cys 38]PTHrP(7–38) and PTHrP(7–34)amide had similar receptor affinities (apparent K ds: 5 × 10 −8 M and 8 × 10 −8 M), while that of [Nle 8,18,Tyr 34]bPTH(7–34)amide was more than 10-fold lower (apparent K d: 2 × 10 −6 M). These changes in biological properties suggest that high affinity receptor binding requires both amino- and carboxyl-terminal domains of the PTHrP(1–36) sequence and/or intramolecular interactions which are impaired by the D-Trp substitution for Gly 12. 相似文献
19.
Recent pharmacological data strongly support the hypothesis of δ receptor subtypes as mediators of both supraspinal and spinal antinociception (δ 1 and δ 2 receptors). In vitro ligand binding data, which are fully supportive of the in vivo data, are still lacking. A previous study indicated that [ 3H][
-Ala 2,
-Leu 5]enkephalin labels two binding sites in membranes depleted of μ binding sites by pretreatment with the site-directed acylating agent, 2-( p-ethoxybenzyl)-1-diethylaminoethyl-5-isothiocyanatobenzimidazole-HCI (BIT). The main goal of the present study was to develop a ligand-selectivity profile of the two δ ncx binding sites. The data indicated that naltrindole and oxymorphindole were relatively selective for site 1 (20-fold). [
-Ser 2,Thr 6]Enkephalin and deltorphin-II were only 2.7-fold and 2.2-fold selective for site 1. [
-Pen 2,
-Pen 5]Enkephalin and deltorphin-I were 80-fold and 38-fold selective for site 2.3-Iodo-Tyr-
-Ala-Gly-Phe-
-Leu was 52-fold selective for site 1. Morphine had moderate affinity for site 1 ( Ki = 16 n M), and was about 11-fold selective for site 1. Thus, of the 10 drugs studied, only DPDPE and DELT-I were selective for site 2. Viewed collectively with other data, it is likely that the δ 1 receptor and the δ ncx binding site are synonymous. 相似文献
20.
Neuropeptide Y (NPY) is involved in the regulation of emotionality including fear and anxiety, which modulate autonomic control of cardiovascular function. We therefore investigated the central effects of porcine NPY, selective Y 1, Y 2 and Y 5 receptor agonists and a Y 1 receptor antagonist on heart rate (HR) and HR variability in freely moving mice using auditory fear conditioning. Intracerebroventricular (i.c.v.) injections were applied 15 min before the tone-dependent memory test. NPY dose-dependently induced bradycardia associated with decreased HR variability, and blunted the stress-induced tachycardic response. The selective Y 1 receptor antagonist BIBO 3304 blocked the NPY- and Y 1-receptor agonist-induced suppression of conditioned tachycardia without affecting basal HR. The tachycardia elicited by both conditioned and unconditioned stressor was effectively attenuated by the Y 1 receptor agonist. These results suggest a specific contribution of Y 1, but not Y 2 and Y 5 receptors, to modulation of emotional responses most likely unrelated to impairment or modulation of memory. The NPY-induced bradycardia is attributed to not yet characterized NPY receptor subtypes other than Y 1, Y 2 and Y 5, or a complex receptor interaction. In conclusion, NPY mediates central inhibition of sympathetic outflow, potentially coupled with attenuation of parasympathetic tone, i.e., mechanisms that may be associated with the reported anxiolytic action. 相似文献
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