Selectivity and potency of new basic CCK-B antagonists.
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Animals↗
Biomedical subjects
F Makovec
Publications and source records attributed to F Makovec.
CR 2039, a new bis-(1H-tetrazol-5-yl)phenylbenzamide derivative with potential for the topical treatment of asthma.
The pharmacological activity of CR 2039 (4-(1H-tetrazol-5-yl)-N-(4-[1H-tetrazol-5-yl]phenylbenzam ide)) a newly discovered antiallergic compound is described. CR 2039 administered i.m. or i.v. inhibited rat passive cutaneous anaphylaxis (PCA) with an ED50 of 0.1 mg/kg and a potency about 15 times higher than that of disodium cromoglycate (DSCG). CR 2039 i.m., by aerosol or as dry powder insufflation, gave dose-related significant protection against IgE-dependent bronchial anaphylaxis induced by aerosolized antigen in anesthetized guinea-pigs. In conscious guinea-pigs CR 2039 given i.m. delayed dose dependently (ED50, 17 mg/kg) the onset of bronchoconstriction induced by aerosolized antigen, while DSCG was ineffective up to 100 mg/kg. The protection was accompanied by significant inhibition of the vascular permeability provoked by antigen challenge in all airway segments except trachea. CR 2039 (10-100 mg/kg i.v.) inhibited the microvascular permeability changes in a model of allergic conjunctivitis in sensitized guinea-pigs. CR 2039 inhibited dose dependently guinea-pig lung cAMP-phosphodiesterase with an IC50 of 50 microM.
3',5'-Cyclic-AMP Phosphodiesterases↗
Antiallergic and cytoprotective activity of new N-phenylbenzamido acid derivatives.
A series of new N-phenylbenzamido acid derivatives was synthesized and evaluated for their ability to inhibit the IgE-mediated passive cutaneous anaphylaxis in the rat (PCA), as well as for their capacity to inhibit gastric mucosal damage induced by the oral administration of absolute alcohol in the rat. Some of these new derivatives exhibit potent antiallergic and cytoprotective activity, 20-80 times higher than that of the reference, disodium cromoglycate (DSCG). Structure-activity relationships are discussed. The antiallergic activity of one of the more potent compounds of this series, i.e. 4-(1H-tetrazol-5-yl)-N-[4-(1H-tetrazol-5-yl)phenyl]benzamide (compound 44, CR 2039) was further evaluated in vivo. This compound antagonizes the bronchoconstriction induced by aerosolized ovalbumin in both anesthetized and conscious IgE sensitized guinea pigs with ID50 of 3.7 mg/animal (tracheal insufflation) and 20 mg/kg (im). Further cytoprotective effects were evaluated in gastric ulcer models induced by the acute oral administration of hypertonic sodium chloride solution or by acetic acid and by the subchronic administration of glucose in fasted animals. In the models used experimentally CR 2039 is effective, whereas DSCG seems to be devoid of any protective activity. Such a potent antiallergic and mucosal protectant could provide a new potential agent in the therapy of atopic allergic diseases.
Animals↗
Characterization of antigastrin activity in vivo of CR 2194, a new R-4-benzamido-5-oxo-pentanoic acid derivative.
The antigastrinic activity, in vivo, of CR 2194 (R-4-(3-chlorobenzamido)-5-(8-azaspiro[4.5]decan-8-yl) -5-oxo pentanoic acid) was assessed in various animal species. CR 2194 antagonized pentagastrin-stimulated gastric acid secretion in the rat (ID50 = 11 mg/kg i.v.), dog (ID50 = 5.9 mk/kg i.v. or 28.8 mg/kg os) and cat (ID50 = 15.5 mg/kg i.v.). CR 2194, in the cat, inhibited both competitively and non-competitively the gastric acid secretion stimulated with increased doses of pentagastrin, with a pA2 of 4.89. In the rat and in the dog the antagonism seemed to be non-competitive and the respective pD'2 calculated were 4.54 and 4.42. The interaction of CR 2194 with the gastrin receptors appeared reversible, as demonstrated by the return to normal values of the acid output after the conclusion of the i.v. infusion, during pentagastrin continuous stimulation in the dog. The antigastrin activity was specific: CR 2194 was unable to antagonize the gastric acid secretion stimulated by carbachol or histamine in the rat up to the dose of 100 mg/kg. CR 2194 was effective to antagonize the gastric acid secretion stimulated by gastrin release after meal ingestion in the Heidenhain pouch dog model. The ID50 calculated was 2.89 mg/kg after oral administration. All these characteristics make CR 2194 an important compound in the investigation of the biological effects of gastrin and a potential agent for diagnostic or therapeutic use.
Animals↗
Structure-antigastrin activity relationships of new (R)-4-benzamido-5-oxopentanoic acid derivatives.
New (R)-4-benzamido-5-oxopentanoic acid derivatives were synthesized by a stereoconservative procedure and evaluated in vitro for their capacity to inhibit the binding of [125I](BH)-CCK-8 to either rat peripheral (CCK-A) or central (CCK-B) CCK receptors, or the binding of [3H]pentagastrin to rabbit gastric glands, as well as to inhibit, in vivo, the acid secretion induced by pentagastrin infusion in the perfused rat stomach. The parent compound of this series (lorglumide) is the first nonpeptidic, potent and selective antagonist of the CCK-A receptor. Chemical manipulations of the structure of lorglumide led to the discovery of selective antagonists of the CCK-B/gastrin receptors. Structure-activity relationships are discussed. Some of these new derivatives exhibit different affinities with rabbit gastric gland cells and rat cortex membranes, suggesting that the stomach gastrin receptor (arbitrarily termed CCK-B1 receptor) is not as closely related to the CCK central receptor (termed CCK-B2) as previously hypothesized. The antigastric activity of the most potent compound of the series, i.e. (R)-4-(3,5-dichlorobenzamido)-5-(8-azaspiro[4.5]decan- 8-yl)-5-oxopentanoic acid (compound 28, CR 2194) was further evaluated in vivo: in the first hour after administration the compound inhibits acid secretion induced by pentagastrin infusion, in both cat and dog (in the cat with gastric fistula and in the dog with Heidenhain pouch), with ID50s (mg/kg) of 15.5 (iv) (cat), 8.7 (IV) (dog) and 24.2 (oral) (Heidenhain dog). The characteristics of CR 2194, that is, the selectivity for the gastrin receptor, the simple nonpeptidic molecular structure, and the activity after oral administration, indicate that this compound is a useful tool in the study of the biological effects of gastrin and a potential agent for diagnostic or therapeutic use.
Animals↗
Therapeutic effect of the gastrin receptor antagonist, CR2093 on gastrointestinal tumour cell growth.
The gastrin receptor antagonist, CR2093, competed with 125I-gastrin-17 (5 x 10(-10) M) for binding to gastrin receptors on the rat pancreatic adenocarcinoma, AR42J (CR2093 concentration inducing 50% of 125I-gastrin-17 binding (IC50) was 8 x 10(-5) M), on the human gastric adenocarcinoma, MKN45 (IC50 5.5 x 10(-5) M) and the human colo-rectal adenocarcinoma C523 (IC50 greater than 10(-4) M). Intravenous administration of CR2093 (40 mg kg-1 day-1) reduced the gastrin-17 stimulated growth of AR42J xenografts in nude mice to below that of the original basal growth (P = 0.0166 from basal and P = 0.0109 from gastrin stimulated growth). CR2093 administration also reduced the gastrin-stimulated growth of MKN45 xenografts (P = 0.045) but failed to inhibit the gastrin enhanced proliferation of C523 xenografts. This may be related to the affinity (Kd) of the gastrin receptors present on the xenograft lines as the Kds of the two xenografts inhibited by CR2093 were 4.6 x 10(-10) M (AR42J) and 1.2 x 10(-9) M (MKN45) respectively whereas the Kd of C523 was of higher affinity (2.2 x 10(-10) M). GR antagonists may be a viable therapeutic option for gastrin receptor positive, gastro-intestinal tumours.
Amino Acids↗
Antispasmodic activity of tiropramide.
Tiropramide hydrochloride and some of its metabolites were studied in vivo for their antispasmodic activities on the following models: gastric emptying in the mouse retarded by cholecystokinin octapeptide (CCK-8) or morphine, progression of intestinal contents in the mouse, spontaneous motility of the colon in the anesthetized rabbit, diarrhea induced by castor oil in the rat, spasm of the sphincter of Oddi provoked by morphine in the guinea pig, contractions of the urinary bladder in the anesthetized rat. On these models tiropramide had an antispasmodic activity at doses of 4-40 mg/kg i.p. or i.v. and of 50-90 mg/kg orally. The potency was greater on "pathological" contractions or spasms and smaller on "physiological" movements. Tiropramide may therefore be regarded as a "eukinetic" antispasmodic agent. Tiropramide in general was more potent than reference agents such as papaverine or flavoxate and was active also after oral administration. The metabolites of tiropramide, i.e. CR 1034, CR 1098 and CR 1166 showed similar pharmacodynamic effects, but their potency was smaller than that of tiropramide. Large doses of tiropramide have depressive actions on the cardiovascular system, which can be seen especially if tiropramide is administered i.v. and are less pronounced after oral administration. The circulatory effects are therefore probably the limiting factor for increasing the parenteral doses of tiropramide in human therapy. Tiropramide was found less toxic than papaverine (LD50). The metabolites of tiropramide were less toxic than the parent compound. The toxicity of the chiralic forms of tiropramide does not differ significantly from that of the racemic substance.
Animals↗
Pharmacological characterisation of the smooth muscle antispasmodic agent tiropramide.
(+/-) Tiropramide hydrochloride, its D and L optical isomers and some of its metabolites were characterized in a number of in vitro pharmacological tests. Tiropramide showed broad spectrum antispasmodic activities on the isolated stomach of guinea pig electrically stimulated; on the longitudinal muscles of the ileum of guinea pig stimulated by electrical impulses, BaCl2, acetylcholine, histamine, serotonin, substance P and cholecystokinin octapeptide (CCK-8); on the spontaneous contractions and on the electrical inhibition of the jejunum of rabbit; on the spontaneous contractions and on the contractions provoked by BaCl2 and acetylcholine of the ascending colon of the rat; on the contractions provoked by BaCl2, acetylcholine, histamine and cerulein of the circular muscles of the gall bladder of the guinea pig; on the spontaneous contractions of the pyel-ureter preparation of the guinea pig; on the contractions of the uterus of the rat provoked by oxitocin, serotonin, acetylcholine, PGF2; on the spontaneous contraction of the portal vein of the rat; on the constriction of the tail artery of the rat provoked by electrical stimulation, epinephrine and ergotamine; on the contractions of the aortic strip of the rabbit stimulated by norepinephrine; on the contractions of the strip of bovine coronary artery depolarized by HCl. In general tiropramide had antispasmodic effect at 5-60 mumol/l concentration. It was more potent than papaverine on contractions provoked by electrical or chemical stimuli, and was less potent or ineffective on spontaneous and "physiological" contractions of the different smooth muscle preparations. Tiropramide had small effects on vascular smooth muscles and showed very small calcium channel blocking activity.
Animals↗
Metabolism and excretion of 14C-tiropramide after single intravenous or peroral administration to the rat.
The study was performed with 14C-tiropramide hydrochloride, i.e. O-(2-diethylamino-ethyl)-N-benzoyl-[DL-(U-14C)tyrosyl]-dipropylamide+ ++ hydrochloride, with a specific activity of 466.16 microCi/mmol. For the study of pulmonary, urinary and fecal excretion the substance was administered in single intravenous (i.v.) doses of 4 mg/kg to 4 rats (2 males and 2 females) and in single peroral (p.o.) doses of 10 mg/kg to other 4 rats (2 males and 2 females). For the study of biliary excretion 4 mg/kg of 14C-tiropramide hydrochloride were administered in single i.v. doses to 4 rats (2 males and 2 females) anesthetized with urethane and the bile was collected from the choledocus in the 8 h following administration. The radioactivity in the expired CO2, urine feces and bile was measured by scintillometry. The radioactive substances were extracted, separated by TLC and identified by comparison of their Rf values with those of putative metabolites with known chemical structure. The following results were obtained. Radioactivity in the expired CO2: No radioactivity was found, either after i.v. or p.o. administration. Radioactivity in urine: In the 48 h after administration 37% of the i.v. administered radioactivity and 31% of the p.o. administered radioactivity was recovered in the urine. Six basic substances could be identified. In order of decreasing abundance these were CR 1166, CR 1098, tiropramide, CR 1034, CR 1919 and CR 1938. Radioactivity in feces: In the 120 h after administration 60% of the i.v. administered radioactivity and 56% of the p.o. administered radioactivity was recovered in the feces.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Oral↗
Distribution of tiropramide and metabolites after single intravenous or peroral administration of 14C-tiropramide to the rat.
The study was performed with 14C-tiropramide hydrochloride, i.e. O-(2-diethylamino-ethyl)-N-benzoyl-[DL-(U-14C)tyrosyl]-dipropylamide+ ++ hydrochloride, with a specific activity of 466.16 microCi/mmol. The substance was administered in single intravenous (i.v.) doses of 4 mg/kg to 16 rats (8 males and 8 females) and in single peroral (p.o.) doses of 10 mg/kg to other 16 rats (8 males and 8 females). The radioactivity in plasma, in several organs and tissues and in gastrointestinal contents was measured by scintillometry. After i.v. administration the radioactivity is rapidly found in all investigated organs and tissues and also in the stomach contents. The radioactivity is concentrated in the liver and kidney, and also in other organs, as the pancreas and the salivary glands. After 120 h the radioactivity is small in the organs but still appreciably present in the colon content. The radioactivity crosses the blood-brain barrier. Deep compartments were not found. After p.o. administration the radioactivity is rapidly found in the organs and is particularly concentrated in the liver, showing a rapid absorption from the gastrointestinal tract. Besides the obvious higher concentration of radioactivity in the stomach and small intestine in the initial times after p.o. administration, the distribution and elimination pattern from the organs do not substantially differ from those found after i.v. administration. The distribution pattern found using the scintillographic method were confirmed by an autoradiographic study made on 12 non-pregnant rats (10 males and 2 females) and on 7 rats at the 13th day of pregnancy and 7 rats at the 18th day of pregnancy.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Oral↗
Identification of metabolites of tiropramide in human urine.
The metabolites of tiropramide were extracted from the urine of healthy volunteers given tiropramide hydrochloride orally. Eight metabolites of tiropramide were found by gas chromatography/mass spectrometry. Three were identified on the basis of their mass spectra, retention times and comparison with synthetic standards. For the others a probable structure is proposed on the basis of their mass spectra.
Adult↗
Calcium antagonists: vinylogues and bivalent ligands related to nifedipine.
The synthesis and the pharmacological properties of some vinylogues and bivalent ligands related to nifedipine are described.
Administration, Oral↗
Tiropramide and metabolites in blood and plasma after intravenous or peroral administration of 14C-tiropramide to the rat.
The study was performed with 14C-tiropramide hydrochloride (O-(2-diethylamino-ethyl)-N-benzoyl-[DL-U-14C-tyrosyl]-dipropyl-amide hydrochloride) with a specific activity of 466.16 muCi/mmol. The substance was administered in single i.v. doses of 4 mg/kg to 18 male and 18 female rats or p.o. doses of 10 mg/kg to 16 male and 16 female rats. The radioactivity in blood and plasma was measured by scintillometry. The radioactive substances were extracted, separated by TLC and identified by comparison of their Rf values with those of putative metabolites with known chemical structure. After i.v. administration the parent substance tiropramide and 5 metabolites were identified in plasma. Tiropramide was the most abundant substance with an AUC equal to 51% of the AUC of total radioactivity. After p.o. administration the parent tiropramide and 5 metabolites were identified. Tiropramide was the most abundant substance till the 1st h. Then the metabolite CR 1098 ((+-)a-benzoylamino-4-(2-ethylamino-ethoxy)-N, N-dipropyl-benzenepropanamide) prevailed. The Cmax of tiropramide was reached at 0.5 h with 1183 nmol/l. The AUC of tiropramide was 19% of the AUC of total radioactivity. It appears that after p.o. administration the biotransformation of tiropramide is more intense than after i.v. administration. The absolute bioavailability of total radioactivity calculated on the ratio between the p.o. and i.v. AUC was 0.67, that of tiropramide was 0.23. The difference between the absolute bioavailability of total radioactivity and that of tiropramide is probably due to a first-pass effect and a more intense biotransformation of the substance after p.o. administration.
Administration, Oral↗
Pharmacokinetics of loxiglumide after single intravenous or oral doses in man.
Loxiglumide (D,L-4-(3,4-dichlorobenzoylamino)-5-(N-3-methoxypropyl-pentylam ino)-5-oxo-pentanoic acid, CR 1505) was given intravenously to 8 male healthy volunteers in a single dose of 2 mg/kg body weight (b.w.) or orally in a single dose of 5 mg/kg b.w. Loxiglumide was measured in plasma and in urine by HPLC during 48 h following the administration. After i.v. infusion the plasma levels were consistent with an open two-compartment pharmacokinetic model represented by the equation C (mg/l) = 43.791 x e-2.652 x h + 2.657 x e-0.139 x h. In the urine, besides loxiglumide, two metabolites were found and in the 48 h following the i.v. administration the urinary excretion of loxiglumide and of its metabolites accounted for 11.13% of the administered dose. After oral administration loxiglumide appeared in plasma with a lag time of 14 min, reached the peak 34 min after administration, being eliminated with an initial fast and a terminal slow elimination rate. The plasma levels were consistent with an open two-compartment pharmacokinetic model represented by the equation C (mg/l) = -46.72 x e-8.765 x (h-0.23) + 40.660 x e-1.383 x (h-0.23) + 6.057 x e-0.120 x (h-0.23). In the urine, besides loxiglumide, two metabolites were found and in the 48 h following the oral administration the excretion of loxiglumide and of its metabolites accounted for 7.67% of the administered dose. The absolute bioavailability of loxiglumide was calculated comparing the AUC(0-inf) found after oral and after i.v. administration and was estimated as 0.967, with p = 0.05 fiducial limit of 0.656-1.278.
Administration, Oral↗
Antispasmodic activity on the gallbladder of the mouse of CR 1409 (lorglumide) a potent antagonist of peripheral CCK.
Cholecystokinin (CCK) is a hormonal regulator of the motility of the gallbladder. CCK-8, i.e. the biologically active C-terminal octapeptide of the hormone, elicits contraction and emptying of the gallbladder. Endogenous CCK released by egg yolk or fatty acids in the duodenum gives the same results. CR 1409 (lorglumide), a glutaramic acid derivative with peripheric competitive CCK-antagonistic activity, was evaluated in comparison with proglumide (the model CCK-receptor antagonist) and other conventional antispasmodic drugs, for their ability to inhibit the emptying of the gallbladder induced in mice by CCK-8 or by lyophylized egg yolk. CR 1409 (1-10 mg/kg) prevented dose-dependently the emptying of the gallbladder in both experimental models; proglumide exhibited a comparable activity at much higher doses (200-800 mg/kg). On the contrary the anticholinergic drug atropine, the calcium-antagonist nifedipine, and the phosphodiesterase inhibitor papaverine were almost ineffective. The present data support the hypothesis that the effects of CCK on gallbladder motility are mediated by a CCK-dependent specific mechanism.
Animals↗
Anticholecystokinin activities of loxiglumide.
The anticholecystokinin activities of loxiglumide, (D,L-4-(3,4-dichloro-benzoylamino)-5-(N-3-methoxypropyl-pentylamino++ +)-5-oxo- pentanoic acid, CR 1505) are described. Loxiglumide antagonizes in vivo the contractions of the gall bladder of guinea pig induced or mediated by cholecystokinin-8 (CCK-8) (i.v. ED50 = 0.24 mumol/kg), the emptying of the gall bladder of the mouse induced by CCK-8 (i.v. ED50 = 29 mumol/kg, oral ED50 = 42 mumol/kg), the retardation of gastric emptying of the rat induced by CCK-8 (i.p. ED50 = 13 mumol/kg), the retardation of the pyloric transit in the mouse induced by CCK-8 (i.v. ED50 = 3.7 mumol/kg, oral ED50 = 11 mumol/kg), the hypermotility of the ileum of the rabbit induced by CCK-8 (i.v. ED50 = 1.2 mumol/kg) and the contractions of the gall bladder of the non-anesthetized dog induced by caerulein (i.v. ED50 ca. 11 mumol/kg). Loxiglumide also antagonizes the satiety behaviour of the rat elicited by CCK-8 (i.p. ED50 = 0.65 mumol/kg) and the exocrine pancreatic hypersecretion in the anaesthetized dog induced by CCK-8 (i.v. ED50 ca. 0.35 mumol/kg). Loxiglumide has a simple, non-polypeptidic chemical structure and is active after parenteral and after oral administration.
Anesthesia↗
Loxiglumide protects against experimental pancreatitis.
Loxiglumide (D,L-4-(3,4-dichloro-benzoylamino)- 5-(N-3-methoxypropyl-pentylamino)-5-oxo-pentanoic acid, CR 1505) is a derivative of pentanoic acid and belongs to a newly discovered class of agents with cholecystokinin antagonistic activities. Loxiglumide has preventive effects on different types of experimental pancreatitis, induced e.g. by ceruletide (i.p. ED50 ca. 9 mumol/kg), by intrapancreatic taurocholate (i.p. ED50 ca. 80 mumol/kg) or by choline-deficient ethionine-supplemented diet (i.p. ED50 ca. 45 mumol/kg). Loxiglumide has a simple, non-polypeptidic chemical structure and may be a candidate for clinical investigations in man, e.g. for pancreatitis.
Animals↗
Pharmacological properties of lorglumide as a member of a new class of cholecystokinin antagonists.
Derivatives of 5-(dipentylamino)-5-oxo-pentanoic acid are a new class of non-peptide cholecystokinin (CCK) antagonists. The most potent compound, D,L-4-(3,4-dichlorobenzoylamino)-5-(dipentylamino)-5-oxo-pen tanoic acid (lorglumide, CR 1409), has a great affinity for the pancreatic CCK receptors and is a competitive, specific and potent CCK antagonist on the smooth muscles of the gall bladder and ileum of the guinea pig and on the CCK-induced amylase secretion of isolated pancreatic acini. In vivo lorglumide antagonizes the contraction of the gall bladder of the guinea pig and of the dog provoked by i.v. CCK-8 or ceruletide (caerulein). It antagonizes the satiety effect of CCK-8 in the rat and is protective against ceruletide-, taurocholate- and diet-induced pancreatitis. Lorglumide is therefore a useful pharmacological tool to study the functions of CCK. For its pharmacological properties, its relatively low toxicity and because it is active also after oral administration, lorglumide is a candidate for diagnostic or therapeutic use in man when an involvement of CCK is suspected.
Animals↗