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C Durieux

Publications and source records attributed to C Durieux.

At least 37 records · Page 2Linked to original sources
PubMed1994

Antidepressant-like effects of CCKB antagonists in mice: antagonism by naltrindole.

1. The effects of selective CCKB agonists, BC 264 and BC 197 were investigated in the conditioned suppression of motility test in mice, an animal model used to select antidepressant drugs. The results showed that both CCKB agonists at doses of 3 and 30 micrograms kg-1, accentuated the suppression of motility in shocked mice and did not modify the behaviour of non-shocked mice. The effects of BC 264 were suppressed by L-365,260. 2. L-365,260 alone, at doses of 0.2 and 2 mg kg-1 decreased motor inhibition in shocked mice and had no effect in non-shocked mice. 3. The effects of L-365,260 observed in shocked mice were suppressed by naltrindole, a selective antagonist for delta-opioid receptors, suggesting the occurrence of physiological adverse interactions between CCK and opioid systems. 4. Together, these results suggest that CCKB antagonists could block centrally located CCKB receptors to produce antidepressant-like effects which could indirectly involve delta-opioid receptor stimulation.

Amino Acid Sequence↗
PubMed1993

Cholecystokinin peptidomimetics as selective CCK-B antagonists: design, synthesis, and in vitro and in vivo biochemical properties.

Antagonists of cholecystokinin-B (CCK-B) receptors have been shown to alleviate CCK4-induced panic attacks in humans and to potentiate opioid effects in animals. The clinical use of these compounds is critically dependent on their ability to cross the blood-brain barrier. In order to improve this property, new, peptoid-derived CCK-B antagonists, endowed with high affinity, selectivity, and increased lipophilicity have been developed. The affinity and selectivity of these compounds have been characterized in vitro and in vivo using guinea pig, rat, and mouse. Most of these compounds proved to be selective for the CCK-B receptor, the most potent analog, N-[N-[(2-adamantyloxy)carbonyl]-D-alpha- methyltryptophanyl]-N-[2-(4-chlorophenyl)ethyl]glycine (26A), having a Ki value of 6.1 nM for guinea pig cortex membranes in vitro and a good selectivity ratio (Ki CCK-A/Ki CCK-B = 174). Furthermore, the in vivo affinity of 26A for mouse brain CCK-B receptors, following intracerebroventricular injection at different concentrations, was found to be 10 nmol. Using competition experiments with the specific CCK-B ligand [3H]pBC 264, compound 26A was shown to cross the blood-brain barrier (0.2%) after intraperitoneal administration in mice. This compound is therefore an interesting pharmacological tool to further elucidate the physiopathological role of endogenous CCK.

Adamantane↗
PubMed1993

Involvement of D2 dopaminergic receptors in the emotional and motivational responses induced by injection of CCK-8 in the posterior part of the rat nucleus accumbens.

When CCK-8 was injected in the rat posterior nucleus accumbens, where it is in part co-localized with dopamine, a decrease in exploration of the four hole box and the elevated plus maze was observed. In this study, a selective destruction of the dopaminergic mesoaccumbens pathway induced by local injection of 6-hydroxydopamine (6-OHDA) in the nucleus accumbens was found to suppress the CCK-8-evoked behavioral effects. Moreover, an ex vivo measurement of the dopaminergic metabolism has been performed after injection of CCK-8 in the posterior nucleus accumbens by electrochemical detection of dopamine and its metabolites extracted from punches of brain tissue. The results showed that CCK-8 decreased the turnover of dopamine in the posterior part but not in the anterior part of the nucleus accumbens or in the ventral tegmental area. Furthermore, sulpiride, a selective antagonist for D2 dopamine receptors, but not SCH 23390, a selective antagonist for D1 dopamine receptors, prevented CCK-8-induced behavioral responses. Taken together, these results suggest that CCK-8 could be involved in behavioral adaptation to situations producing change in emotional and/or motivational states through modulation of presynaptic D2 receptor functioning.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

CCK-B agonist or antagonist activities of structurally hindered and peptidase-resistant Boc-CCK4 derivatives.

Replacement of Met31 by (N-Me)Nle in CCK8 or CCK4 has been shown to improve the affinity and selectivity for CCK-B receptors. In order to obtain molecules with enhanced bioavailability, two novel series of protected tetrapeptides of the general formula Boc-Trp30-X-Asp-Y33 have been developed. Introduction of (N-Me)Nle and the bulky, aromatic naphthylalaninamide (Nal-NH2) in positions X and Y, respectively, does not greatly modify the affinity for guinea pig brain CCK-B receptors. In contrast, incorporation of hindering N-methyl amino acids such as (N-Me)Phe, (N-Me)Phg, or (N-Me)Chg, but not their non-methylated counterparts, in position X induced a large decrease in affinity for the CCK-B binding sites. Among the various peptides synthesized, Boc-[(N-Me)Nle31,1Nal-NH2(33)]CCK4 (2) (KI = 2.8 nM), Boc-[Phg31,1Nal-NH2(33)]CCK4 (15) (KI = 14 nM), and Boc-[Phg31,1Nal-N(CH3)2(33)]CCK4 (17) (KI = 39 nM) displayed good affinities for brain CCK-B receptors and had good selectivity ratios. These pseudopeptides, in which the presence of unnatural and hydrophobic residues is expected to improve their penetration of the central nervous system, were shown to be very resistant to brain peptidases. Interestingly, whereas compounds 2 and 15 proved to be full agonists for rat hippocampal CCK-B receptors when measured in an electrophysiological assay, compound 17 behaved as a potent antagonist in the same test and displayed a good affinity in rat brain KI(CCK-B) = 51 nM as compared to the Merck antagonist L365,260,KI(CCK-B) = 12 nM. This illustrates a simple means to obtain CCK-B antagonists and suggests that the free, CONH2 group plays a critical role in the recognition of the agonist state of brain CCK-B receptors.

Amino Acid Sequence↗
PubMed1992

Replacement of Tyr-SO3H by a p-carboxymethyl-phenylalanine in a CCK8-derivative preserves its high affinity for CCK-B receptor.

The sulfated tyrosine present in the sequence of CCK8 Asp26-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-PheNH2, seems to play a critical role in the recognition of CCK-A binding sites. In this work, we have investigated whether the presence of an anionic charge on the tyrosine moiety is strictly necessary and whether the sulfate moiety interacts with a divalent cation in the receptor subsite. For this purpose, the novel amino acids (L,D)Phe(p-CH2CO2H) and (L,D) Phe(p-CH2CONHOH), as well as their L-resolved forms were introduced into the sequence of Ac[X27, Nle28, Nle31]-CCK27-33 by solid phase method. The biological activities of these new derivatives were compared to two almost equiactive analogues of CCK8, Ac[Phe(p-CH2SO3H)27, Nle28, Nle31]-CCK27-33 and Boc[Nle28, Nle31]-CCK27-33 (BDNL) and to the nonsulfated analogue of the latter peptide (BDNL NS). All these new CCK-related analogues behave as agonists in stimulating pancreatic amylase release and display high affinity for brain binding sites (KI approximately 3-11 nM) but the only peptides which retain affinity for CCK-A receptors (KI approximately 20 nM) are those containing a p-carboxymethyl phenylalanine. Thus, introduction of this amino acid under an esterified form on the side chain, into specific and potent CCK-B agonists could allow compounds endowed with good bioavailabilities to be obtained.

Amino Acid Sequence↗
PubMed1992

Stimulation of delta-opioid receptors reduces the in vivo binding of the cholecystokinin (CCK)-B-selective agonist [3H]pBC 264: evidence for a physiological regulation of CCKergic systems by endogenous enkephalins.

Cholecystokinin (CCK) and enkephalins appear to be colocalized in several brain structures, and a physiological interaction between these peptides has been suggested by a large number of pharmacological studies. In this work we have shown, by in vivo binding experiments, that the endogenous enkephalins, protected from degrading enzymes by mixed inhibitors such as kelatorphan and N-[(R,S)-2-benzyl-3-[(S)-2-amino-4-methylthiobutyldithio]-1-oxo pro pyl]- L-phenylalanine benzyl ester (RB 101), a systemically active prodrug, modulate CCK release in mouse brain, leading to an overall increase in the extracellular levels of CCK. This was quantified by measuring the effects of both inhibitors on the in vivo binding of [3H]propionyl-Tyr(SO3H)-gNle-mGly-Trp-(N-Me)Nle-Asp-Phe-NH2 ([3H]pBC 264), a selective and highly potent CCK-B agonist. Thus, intracerebroventricular injection of kelatorphan produced a dose-dependent inhibition of the in vivo binding of [3H]pBC 264 with a maximal effect (40%) at 50 nmol. A similar response was observed after intravenous injection of RB 101 (40 mg/kg). The specific binding of [3H]pBC 264 was also inhibited (25%) by intravenous injection of the selective delta-opioid agonist H-Tyr-D-Cys(StBu)-Gly-Phe-Leu-Thr(OtBu)-OH (BUBUC; 2 mg/kg) but not by the mu-agonist H-Tyr-D-Ala-Gly-(N-Me)Phe-Gly-ol (5 mg/kg), suggesting a preferential involvement of delta-opioid receptors in the modulation of CCK release. This was confirmed by using the selective delta-opioid antagonist naltrindole, which prevented the inhibitory effects of BUBUC and of enkephalin-degrading enzyme inhibitors on [3H]pBC 264 binding.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMed1992

[Study of induced effects by selective CCKB agonists cholecystokinin in the nociception and behavior in rodents].

Potent and selective CCK-B agonists with good bioavailability have been designed by modifying the natural CCK-8 peptide. Thus, BC 264 [Boc-Tyr(SO3H)-gNle-mGly-Trp-Me(Nle)-Asp-PheNH2] is a highly potent (0.15 nM) and selective agonist for CCK-B receptors which cross the blood brain barrier. Following i.v. injection of [3H]pBC 264 in mouse, the ligand was found in its intact form in brain tissue. Analgesic studies and in vivo binding experiments have shown that the CCKergic system could modify the release of endogenous enkephalins, whereas mu and delta opioid receptor activation modulates the release of endogenous CCK. Behavioural studies performed after local injection of CCK-8 or BC 264 into the postero-median part of the nucleus accumbens have shown the involvement of CCK-A receptors in motivation and/or emotional states of rats. In the anterior part, CCK-B receptor stimulation could be involved in attention and memory processes. BC 264 systemically administered in mice increased fear and/or "anxiety" in the black and white box test. In the elevated plus maze, BC 264 increased the emotional responses of the "anxious" rat and decreased these responses in "non anxious" animals. These results suggest that endogenous CCK could play a critical role in mood modulation through CCK-A/CCK-B receptor stimulation. Dysfunctioning of the CCK-A/CCK-B pathways could be implicated in anxiety and panic attacks.

Animals↗
PubMed1992

CholecystokininA and cholecystokininB receptors in neurons of the brainstem solitary complex of the rat: pharmacological identification.

The brainstem solitary complex, which receives projections from primary sensory afferents of the vagus nerve, appears to be a crucial site for the action of the cholecystokinin octapeptide (CCK8), because both peripheral-type (CCKA) and central-type (CCKB) binding sites are present in this structure. In the present study, we investigated the effects of recently developed receptor-specific pharmacological tools on neurons recorded in rat coronal brainstem slices, to ascertain whether CCK acts differently on each type of receptor. CCK8, which interacts with both binding sites, had three effects on neuronal discharge, brief excitation, prolonged excitation and delayed inhibition. BC 264, a novel CCK analog endowed with high affinity and selectivity for CCKB receptors, produced exclusively prolonged excitation. L-365,260, a novel nonpeptide antagonist of CCKB receptors, blocked the prolonged excitation induced by BC 264 or CCK8. L-364,718, a potent antagonist of CCKA receptors, blocked delayed inhibition and replaced brief CCK8-induced excitation by prolonged excitation. Altogether, these results show that CCK8 exerts, on neurons of the solitary complex, mixed effects due to simultaneous activation of CCKA inhibitory and CCKB excitatory binding sites. The hypothesis that exogenous CCK8 acts, in the solitary complex, through CCKA sites to slow down the motility of the digestive tract and through CCKB sites to modulate anxiety will be developed.

Animals↗
PubMed1992

[3H]pBC 264, a suitable probe for studying cholecystokinin-B receptors: binding characteristics in rodent brains and comparison with [3H]SNF 8702.

[3H]Propionyl-Tyr-(SO3H)-gNle-mGly-Trp-(NMe)Nle-Asp-Phe-NH2 ([3H]pBC 264) (98-100 Ci/mmol), a new peptidase-resistant cholecystokinin (CCK) agonist that is 1000-fold more potent for CCK-B than for CCK-A receptors, interacts, with a similar subnanomolar affinity, with a single class of binding sites (Kd, 0.15-0.2 nM) in brain membranes of mouse, rat, guinea pig, and cat, in Tris and Krebs buffers. The concentration of CCK-A receptors in rodent brain was estimated to be 8-10 fmol/mg of protein, by measurement of the Bmax values of the nonselective agonist [3H] propionyl-CCK8, with or without 10 nM pBC 264 to saturate CCK-B sites. In guinea pig and mouse brain, specific [3H]pBC 264 binding was not affected by NaCl and/or guanyl-5'-yl-imidodiphosphate. In contrast, in rat brain the affinity of [3H]pBC 264 was decreased and the maximal number of binding sites was increased by NaCl and the guanyl nucleotide or by alkaline treatment, suggesting that a proportion of CCK-B receptors are linked to guanine nucleotide-binding proteins. The Bmax of a CCK8 analog, [3H]SNF 8702, was higher (57 fmol/mg of protein) than that of [3H]pBC 264 (40 fmol/mg of protein) in guinea pig brain cortex but not in mouse brain. The relative potencies of various analogs differed among species. The CCK-B antagonist L365,260 was 18-, 30-, and 64-fold less potent than [3H]pBC 264 in guinea pig, mouse, and rat, respectively. PD 134308, a CCK-B antagonist, was 20-fold less potent in rat brain than in guinea pig brain. Likewise, the cyclic analog BC 254 displayed a 30- and 60-fold lower affinity for mouse and rat than for guinea pig brain preparations. Together, these results suggest the presence of CCK-B receptor subtypes. In all tissues, the specific binding of [3H]pBC 264 at its Kd values was very high (75-90%) and higher than that of the hydrophobic CCK-B probe [3H]SNF 8702 (approximately 50%). Therefore, unlike [3H]SNF 8702, [3H]pBC 264 can be used to study preparations with low receptor concentrations, such as rat brain, making this radiolabeled molecule the most appropriate ligand available to date for CCK-B receptor studies.

Amino Acid Sequence↗
PubMed1991

In vivo binding affinities of cholecystokinin agonists and antagonists determined using the selective CCKB agonist [3H]pBC 264.

The respective role of central vs. peripheral CCK-B receptors in the recently reported anxiolytic effects of CCK-B antagonists remains to be firmly established. We therefore investigated the in vivo binding properties of cerebral CCK receptors after i.c.v. injection into mice of [3H]pBC 264 ([3H]propionyl-Tyr(SO3H)-gNle-mGly- Trp-(NMe)Nle-Asp-Phe-NH2), a highly potent, peptidase-resistant and selective CCK-B agonist. The specific binding of [3H]pBC 264 was reversible and saturable. The dose producing 50% receptor occupancy was 25 pmol and the Bmax was 0.9 pmol/brain 15 min after injection. I.c.v. administered CCK8 (ID50 8500 pmol) was 200-fold less potent than pBC 264 (ID50 43 pmol) in inhibiting specific [3H]pBC 264 binding; CCK8NS, CCK5 and CCK4 being slightly less potent than CCK8. Aminopeptidases play a major role in degrading CCK8 since the protected analog pCCK8 or CCK8 in the presence of an aminopeptidase inhibitor exhibited higher affinities than CCK8. I.v. administration of pBC 264 (20 mg/kg) inhibited [3H]pBC 264 specific binding by about 72%, confirming its ability to enter the brain. In contrast, CCK4 was unable to modify [3H]pBC 264 binding. As expected, the CCK-A antagonist (L364,718) did not inhibit [3H]pBC 264 binding, while at the highest dose used (40 mg/kg i.p.) the CCK-B antagonist (L365,260) inhibited binding by 20%. Several hypotheses are discussed to account for the very low i.v. doses of CCK4 and L365,260 needed to produce anxiogenic and anxiolytic responses, respectively.

Amino Acid Sequence↗
PubMed1991

Solid phase synthesis of a fully active analogue of cholecystokinin using the acid-stable Boc-Phe (p-CH2) SO3H as a substitute for Boc-Tyr(SO3H) in CCK8.

Substitution of the -OSO3H group in the sulfated-tyrosine by the non-hydrolyzable-CH2SO3H group was the first described modification of the sulfate ester that does not affect CCK8 activity. In addition to its capacity to mimic the sulfated tyrosine residue, the amino acid Phe(p-CH2SO3Na) was shown to be stable in acidic media, including HF containing mixtures. The synthesis of Boc-Phe(p-CH2SO3Na)-OH in racemic and resolved forms and its introduction into the sequence of CCK8 by solid phase using standard Boc/benzyl synthesis conditions and BOP as coupling reagent is now reported. The two CCK8 analogues containing the L- or the D-Phe(p-CH2SO3Na) residue, obtained in satisfactory yields, were separated by HPLC and the stereochemistry of Phe(p-CH2SO3Na) residue in each peptide was established by NMR spectroscopy and confirmed by a separate solid phase synthesis in which the pure L isomer was used. Both CCK8 analogues displayed high affinities for peripheral and central receptors (KI approximately 1 nM) and proved to be full agonists in the stimulation of pancreatic amylase secretion. The "stabilized-CCK8 peptide", easily prepared by solid phase, could replace the native peptide in biochemical and pharmacological studies. Moreover the modified amino acid Phe (p-CH2SO3Na) could also be used in solid phase synthesis to prepare a wide variety of CCK analogues and more generally, peptides analogues containing the acid-labile O-sulfated tyrosine.

Amino Acid Sequence↗
PubMed1991

Cholecystokinin-A receptor mediation of food intake in cats.

The selective cholecystokinin (CCK)-B-receptor agonist and antagonist, BC 264 and L 365260, respectively, and the CCK-A-receptor antagonist, L 364718, were used to investigate the possible involvement of different classes of CCK receptors in the control of food intake induced by exogenous CCK octapeptide (CCK-8) in the cat with gastric fistula. Intravenous infusion of CCK-8 dose dependently inhibited milk intake under sham-feeding conditions, maximal inhibition reaching 52 +/- 7% (P less than 0.001) with 0.88 nmol.kg-1.h-1. L 364718 prevented this inhibition, whereas L 365260 was ineffective over the dose range tested. The reversal effect of L 364718 on 0.88 nmol.kg-1.h-1 CCK-8-induced inhibition of milk intake was observed at doses as low as 0.44 nmol.kg-1.h-1. The selective CCK-B-receptor agonist, BC 264, in doses ranging from 0.88 to 7 nmol.kg-1.h-1, had no effect on milk intake under sham-feeding conditions, although it dose dependently stimulated gastric acid output. Furthermore, neither L 364718 nor L 365260 (88 nmol.kg-1.h-1 iv) stimulated milk intake when given in the absence of CCK-8. We conclude that exogenous CCK-8 causes satiety in the cat through activation of peripheral CCK-A receptors.

Animals↗
PubMed1991

Centrally administered cholecystokinin suppresses feeding through a peripheral-type receptor mechanism.

Agonists and antagonists selective for the brain-type [cholecystokinin (CCK)-B] and the peripheral-type (CCK-A) CCK receptor were used to localize the site(s) of action at which CCK inhibits food consumption. BC 264, a highly selective CCK-B receptor agonist, did not decrease consumption of a palatable meal when administered either i.p. or into the lateral ventricles of the brain, whereas CCK decreased feeding when administered i.p. at the same doses. CCK decreased feeding when administered i.v.t. at a high dose, 5 micrograms. L-364,718, an antagonist selective for the CCK-A receptor, blocked completely the action of centrally administered CCK, whereas L-365,260, a selective CCK-B receptor antagonist, had no effect on the ability of centrally administered CCK to inhibit feeding. To estimate the quantity of i.v.t. administered CCK which reached the periphery, a tracer of radiolabeled [3H]p-CCK8 ([3H]CCK octapeptide sulfate), combined with unlabeled pCCK8 (5 micrograms) was administered i.c.t. Thirty minutes after administration, intact radiolabeled pCCK8 was extracted from the plasma and measured in the blood in nanomolar concentrations, exceeding the amounts of CCK octapeptide sulfate reported previously to be present in the plasma after a meal. Intraventricularly administered CCK thus appears to reduce feeding in the rat through a mechanism involving a CCK-A receptor subtype in the periphery.

Animals↗
PubMed1990

Investigation of behavioral and electrophysiological responses induced by selective stimulation of CCKB receptors by using a new highly potent CCK analog, BC 264.

The new CCKB analog, Boc-Tyr (SO3H)-gNle-mGly-Trp-(NMe)-Nle-Asp-PheNH2 (BC 264) exhibited a high affinity (KI = 0.39 +/- 0.15 nM) and selectivity for central (B) versus peripheral (A) receptors (KI CCKA/KI CCKB = 910) in the rat. In agreement with these binding studies, BC 264 was at least 50 times more potent than CCK8 in stimulating the firing of rat CA hippocampal neurones. Furthermore stereotaxic injection of BC 264 or CCK8 in the VTA of rats resulted in potentiation of the dopamine-induced hypolocomotion. These two types of CCK8 responses have been previously shown in involve CCKB receptors. In contrast, after administration into the postero-median nucleus accumbens, the hypoexploration, the increase of emotionality of rats, or the potentiation of dopamine-induced hyperlocomotion were obtained after injection of CCK8 but not of BC 264, supporting the involvement of peripheral CCKA receptors in these CCK8 responses. Owing to its resistance to peptidases, BC 264 appears to be of great interest in the investigation of the still uncertain functional roles of CCK in the central nervous system.

Action Potentials↗
PubMed1990

Boc-Trp-Orn(Z)-Asp-NH2 and derivatives: a new family of CCK antagonists.

The respective roles of the benzyloxycarbonyl group (Z) and of the N-terminal tripeptide moiety in the antagonist properties of the cholecystokinin CCK8 analogue Boc-[Nle28,Orn(Z)31]CCK27-33 (Marseigne et al. J. Med. Chem. 1988, 31, 966.) were studied with the following derivatives: Boc-[Nle28,Orn(X)31]CCK27-33, Boc[Nle28,Orn(X)31]CCK27-32, Boc-[Orn(X)31]CCK30-33, and Boc-[Orn(X)31]CCK30-32 (X = Z, Boc, H). These derivatives, the synthesis of eight of which is reported here, were tested for their abilities to inhibit the binding of [3H]pCCK8 to guinea pig pancreatic and brain membranes and for their potencies in stimulating amylase release from guinea pig pancreatic acini. None of the Z derivatives produced amylase secretion, but they competitively antagonized the stimulation induced by CCK8. The deletion of the N-terminal tripeptide and/or Phe-NH2(33) residue did not play a key role in the recognition of peripheral receptors and in the activity of these peptides, whereas replacement of the Z group by a Boc group slightly decreased the affinities of the compounds for both pancreatic and brain binding sites and their potencies as peripheral antagonists. Moreover, the tetrapeptide Boc-Trp-Orn(Boc)-Asp-Phe-NH2 behaved as a partial agonist and analogues in which the Z or Boc groups on the ornithine residue were removed were full agonists. Interestingly, the short peptide derivative Boc-Trp-Orn(Z)-Asp-NH2 displayed the same affinity (KI = 2.0 +/- 0.2 x 10(-7] and the same antagonist activity (pA2 = 6.63) as its parent compound Boc-[Nle28,Orn(Z)31]CCK27-33. This tripeptide could be an interesting tool for studying the structural relationships between peptide and non-peptide CCK antagonists.

Amino Acid Sequence↗
PubMed1989

Conformational behavior of cyclic CCK-related peptides determined by 400-MHz 1H-NMR: relationships with affinity and selectivity for brain receptors.

The conformational study of a homogenous series of cyclic analogues of CCK8, selective for central receptors, such as Boc-X-Tyr(SO3H)-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2, where X = L-Glu, D-Glu, or gamma-D-Glu, was performed by 400-MHz 1H-nmr. The regular increase in affinity for central receptors when going from [L-Glu] to [gamma-D-Glu] is correlated to (a) an enhancement in internal flexibility of the cyclic moiety, (b) an external orientation of the tyrosine side chain, and (c) a restructuring of the C-terminal part of the peptide. All these results could permit a modeling of biologically active conformation of CCK8 for both receptors types to be performed.

Animals↗
PubMed1989

Full agonists of CCK8 containing a nonhydrolyzable sulfated tyrosine residue.

The sulfate ester of CCK26-33 or CCK8 (Asp-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2) borne by the tyrosine residue is a critical determinant of the biological activity of this peptide. In order to increase the stability of this molecule, the sulfated tyrosine has been replaced by a synthetic amino acid (L,D)Phe(p-CH2SO3Na) in which the OSO3H group was replaced by the nonhydrolyzable CH2SO3H group. Both isomers were separated by chromatography and the stereochemistry of the Phe(p-CH2SO3Na) residue in each peptide was established by NMR spectroscopy. The biological activities of the new derivatives Ac[X27, Nle28,Nle31]CCK27-33 were compared with those of Boc[Nle28,Nle31]CCK27-33, an equiactive analogue of CCK8 and Boc[D-Tyr(SO3Na)27,Nle28,Nle31]CCK27-33. Besides their highly enhanced chemical stability, Ac[L-Phe(p-CH2SO3Na)27,Nle28,Nle31]CCK27-33 and Ac[D-Phe(p-CH2SO3Na)27,Nle28,Nle31]CCK27-33 display high affinity for peripheral and central CCK receptors (KI congruent to 10(-9) M) and proved to be full agonists in the stimulation of pancreatic secretion as well as in the in vitro CCK8-induced contractions of the guinea pig ileum.

Amylases↗