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V Daugé

Publications and source records attributed to V Daugé.

44 records · Page 3Linked to original sources
PubMed1989

CCK8 effects on motivational and emotional states of rats involve CCKA receptors of the postero-median part of the nucleus accumbens.

Administration of 3 fmol of cholecystokinin octapeptide (CCK8) into the postero-median nucleus accumbens (NAS) induced an hypoexploration measured using the four-hole box and an increase in the emotional states of rats observed in the elevated plus maze. These effects seem likely to involve CCKA receptors since they were reversed by the selective CCKA antagonist L364,718 (100 micrograms/kg, 200 micrograms/kg IP) and not observed after injection of 0.1 to 1000 fmol unsulfated cholecystokinin octapeptide (CCK8NS) in the same region. On the other hand, CCK8 or CCK8NS injected into the anterior NAS did not significantly modify these behaviors. These results support the neuroanatomical heterogeneity in the distribution of CCK and its binding sites in the NAS, but raise the question of the presence of CCKA receptors not detected in binding studies and of the behavioral effects mediated by CCKB receptor stimulation in this structure.

Animals↗
PubMed1988

Comparison of the behavioural effects induced by administration in rat nucleus accumbens or nucleus caudatus of selective mu and delta opioid peptides or kelatorphan an inhibitor of enkephalin-degrading-enzymes.

The effects of selective agonists for delta opioid receptors: [D-Thr2, Leu5]-enkephalyl-Thr6 (DTLET) and mu receptors: [D-Ala2, MePhe4, Gly-ol5]-enkephalin (DAGO) and of (R)-3-(N-hydroxyl-carboxamido-2-benzylpropanoyl)-L-alanine (kelatorphan), a complete inhibitor of enkephalin degrading enzymes, on the motor activity of rats was examined after their local administration into the nucleus accumbens (NA) or nucleus caudatus (NC). In both structures DTLET dose dependently enhanced locomotor activity as measured in the open-field test. This strong effect was reversed by the selective delta antagonist: ICI 174,864. Contrastingly, DAGO induced hypoactivity followed by hyperactivity 150 min later. This biphasic effect was blocked by systemic injection of naloxone, but not by ICI 174,864. The physiological relevance of these effects was ascertained by the naloxone-reversible stimulatory responses induced by kelatorphan, supporting a role for endogenous enkephalins in the control of behavior through delta receptor stimulation.

Animals↗
PubMed1988

Development of conformationally constrained linear peptides exhibiting a high affinity and pronounced selectivity for delta opioid receptors.

A series of linear conformationally constrained opioid peptides was designed in an attempt to develop highly selective and potent agonists for the delta opioid receptors. These enkephalin analogues corresponding to the general formula Tyr-D-X(OY)-Gly-Phe-Leu-Thr(OZ) were obtained by incorporating bulky residues (X = Ser or Thr; Y = tert-butyl or benzyl; Z = tert-butyl) into the sequence of the previously reported delta specific agonists DSLET (Tyr-D-Ser-Gly-Phe-Leu-Thr) and DTLET (Tyr-D-Thr-Gly-Phe-Leu-Thr). In binding studies based on displacement of mu and delta opioid receptor selective radiolabeled ligands from rat brain membranes, the two constrained hexapeptides, Tyr-D-Ser(O-t-Bu)-Gly-Phe-Leu-Thr (1, DSTBULET) (KI(mu) = 374 nM, Kr(delta) = 6.14 nM, KI(delta)/KI(mu) = 0.016) and in particular Tyr-D-Ser(O-t-Bu)-Gly-Phe-Leu-Thr(O-t-Bu) (7, BUBU) (KI(mu) = 475 nM, KI(delta) = 4.68 nM, KI(delta)/KI(mu) = 0.010) were shown to be among the most potent and selective delta probes reported to date. A roughly similar pattern of selectivity was obtained with the guinea pig ileum and mouse vas deferens bioassays. In addition, the analgesic potency (hot-plate test) of these peptides intracerebroventricularly administered in mice was shown to be significantly related to their mu-receptor affinity.

Animals↗
PubMed1988

Investigation of the structural parameters involved in the mu and delta opioid receptor discrimination of linear enkephalin-related peptides.

The previous rules proposed for selective recognition of mu and delta opioid receptors by modified enkephalins were investigated through an extensive structure-activity study. Thus, modifications of the sequence of TRIMU 4 (Tyr-D-Ala-Gly-NHCH(CH3)CH2CH(CH3)2, a peptide that exhibits mu selectivity close to that of DAGO (Try-D-Ala-Gly-N(Me)Phe-Gly.ol), were performed for two positions, 2 and 4, critical for mu recognition. The drastic loss of potency following introduction of L-Ala or Aib in position 2 emphasizes the importance of the stereochemistry and the steric size of the X2 amino acid for optimal mu binding. The enhancement of the intrinsic flexibility of the C-terminal alkyl chain of TRIMU 4 through removal of a methyl group leads to TRIMU 5 (Tyr-D-Ala-Gly-NHCH2CH2CH(CH3)2), a peptide with a mu selectivity similar to that of DAGO. In contrast, introduction of an O-tert-butyl Ser2 residue increases affinity for delta receptors. In the hexapeptide series derived from DSLET (Tyr-D-Ser-Gly-Phe-Leu-Thr), a D-Thr2 moiety was shown to be very efficient in improving delta recognition and delta selectivity appeared also to be modulated by the nature of the sixth residue. The potencies of the 24 peptides studied to inhibit the electrically evoked contractions of the GPI or MVD are relatively well correlated with their affinities for brain mu or delta receptors labeled with [3H]DAGO or [3H]DSLET, respectively. Moreover, the analgesic potency (hot plate test) of the peptides is related to their affinity for rat brain mu receptors. The wide range of receptor affinities exhibited by the compounds reported here could be useful to study the physiological role of mu and delta receptors.

Analgesics↗
PubMed1986

[3H]DSTBULET, a new linear hexapeptide with both an improved selectivity and a high affinity for delta-opioid receptors.

The binding properties of the new agonist Tyr-D-Ser(OtBu)-Gly-Phe-Leu-Thr, DSTBULET, in rat brain tissue shows that insertion of a bulky t.butyl group into the sequence of DSLET leads to a conformationally-induced large increase in selectivity for delta opioid receptors (KI(delta)/KI(mu) = 0.012). In addition to its similar selectivity to that of the cyclic enkephalins DPDPE and DPLPE, the affinity of [3H]DSTBULET for delta sites (KD = 2.9 nM) is significantly better than that of [3H]DPDPE (KD approximately 10.5 nM) or DPLPE (KI (delta) approximately 19 nM). DSTBULET is therefore the most appropriate probe for both binding studies and pharmacological investigations of delta-receptors as illustrated by a comparison of the analgesic properties of DAGO, DSTBULET and DPLPE.

Animals↗
PubMed1984

Highly selective photoaffinity labeling of mu and delta opioid receptors.

We report the synthesis and photolabeling properties of two highly selective ligands for mu and delta opioid-binding sites: Tyr-D-Ala-Gly-MePhe (pN3)-Gly-ol (AZ-DAMGE) and Tyr-D-Thr-Gly-Phe (pN3)-Leu-Thr (AZ-DTLET). An irreversible inhibition of the electrically induced contractions of mouse vas deferens is caused by irradiation (at 254 nm) of the muscle strip in the presence of AZ-DTLET (1 nM). This phenomenon is antagonized only at large concentrations (10 microM) of naloxone, in accordance with the well-known lower selectivity of naloxone for delta sites. Competition experiments with [3H]DAMGE and [3H]DTLET on crude rat brain membranes showed that the azido photoprobes display a similar (AZ-DAMGE) and even a better (AZ-DTLET) selectivity than their respective parent compounds DAMGE and DTLET. Up to 25 nM, AZ-DTLET irreversibly and selectively photolabels the delta sites of crude rat brain homogenates. Due to its lower affinity AZ-DAMGE provides similar selective photolabeling of the mu sites but at higher concentrations (approximately equal to 0.3 microM). When [3H]DAMGE and [3H]DTLET were used as ligands for mu and delta binding subtypes, respectively, no important change in binding capacity and affinity of one receptor type was observed after photolabeling of the other.

Affinity Labels↗
PubMedDate not supplied

Synthesis and biological activity of Boc [Nle28, Nle31]CCK27-33, a highly potent CCK8 analogue.

A new CCK8 related peptide, Boc[Nle28,Nle31]CCK27-33 (Boc[diNle]CCK7) was synthesized and tested for cholecystokinic activity, at both the peripheral and the central level. This analogue, protected against both chemical oxidation and enzymatic degradation by aminopeptidases, was shown to be equipotent to CCK8 in releasing amylase from rat pancreas fragments. In addition, the EC50 values of Boc[diNle]CCK7 in the guinea pig gallbladder and ileum contraction assays (3.2 nM and 3.0 nM respectively) were similar to those of CCK8 (6.0 nM and 2.0 nM). Moreover both Boc[diNle]CCK7 and CCK8 elicited similar effects on the open field test over the same concentrations range. These results demonstrate the ability of Boc[diNle]CCK7 to be a suitable tool for investigating the physiological role of native CCK8.

Amylases↗