M.-T. Garcia-Lopez

Pharmacological evaluation of IQM-95,333, a highly selective CCKA receptor antagonist with anxiolytic-like activity in animal models

The pyridopyrimidine derivative IQM‐95,333 ((4aS,5R)‐2‐benzyl‐5‐[Nα‐tert‐butoxicarbonyl)L‐tryptophyl]amino‐1,3dioxoperhydropyrido[1,2‐c]pyrimidine), a new non‐peptide antagonist of cholecystokinin type A (CCKA) receptors, has been evaluated in vitro and in vivo in comparison with typical CCKA and CCKB receptor antagonists, such as devazepide, lorglumide, L‐365,260 and PD‐135,158. IQM‐95,333 displaced [3H]‐CCK‐8S binding to CCKA receptors from rat pancreas with a high potency in the nanomolar range. Conversely, the affinity of this new compound at brain CCKB receptors was negligible (IC50>10 μM). IQM‐95,333 was a more selective CCKA receptor ligand than devazepide and other CCKA receptor antagonists. Like devazepide, IQM‐95,333 was a more potent antagonist of CCK‐8S‐ than of CCK‐4‐induced contraction of the longitudinal muscle from guinea‐pig ileum, suggesting selective antagonism at CCKA receptors. IQM‐95,333 and devazepide were also potent inhibitors of CCK‐8S‐stimulated amylase release from isolated pancreatic acini, a CCKA receptor‐mediated effect. The drug concentrations required (IC50s around 20 nM) were higher than in binding studies to pancreas homogenates. Low doses (50–100 μg kg−1, i.p.) of IQM‐95,333 and devazepide, without any intrinsic effect on food intake or locomotion, blocked the hypophagia and the hypolocomotion induced by systemic administration of CCK‐8S, two effects associated with stimulation of peripheral CCKA receptors. IQM‐95,333 showed an anxiolytic‐like profile in the light/dark exploration test in mice over a wide dose range (10–5,000 μg kg−1). Typical CCKA and CCKB antagonists, devazepide and L‐365,260 respectively, were only effective within a more limited dose range. In a classical conflict paradigm for the study of anxiolytic drugs, the punished‐drinking test, IQM‐95,333, devazepide and L‐365,260 were effective within a narrow dose range. The dose‐response curve for the three drugs was biphasic, suggesting that other mechanisms are operative at higher doses. In conclusion, IQM‐95,333 is a potent and selective CCKA receptor antagonist both in vitro and in vivo with an anxiolytic‐like activity in two different animal models, which can only be attributed to blockade of this CCK receptor subtype.

Ketomethylene and Methyleneamino Pseudopeptide Analogues of Insect Allatostatins Inhibit Juvenile Hormone and Vitellogenin Production in the Cockroach Blattella germanica

Metabolic studies on insect allatostatins have suggested that the dipeptide Leu-Tyr may be a target for endopeptidases. In order to increase resistance to degradation, methyleneamino psi [CH2NH] and ketomethylene psi [COCH2] peptide bond surrogates have been introduced at the position Leu3-Tyr4 of the allatostatin Asp-Arg-Leu-Tyr-Ser-Phe-Gly-Leu-amide (BLAST-2), and Leu3-Phe4 of [Phe4]BLAST-2, respectively. Assays of inhibition of juvenile hormone (JH) synthesis in vitro by corpora allata from the cockroach Blattella germanica showed that both analogues were similarly active to the respective model peptides. The methyleneamino analogue was further tested in vivo as an inhibitor of JH synthesis, and in vivo and in vitro as an inhibitor of vitellogenin production by the fat body of B. germanica. The analogue was less active than BLAST-2 when tested in vitro, but more active than it when tested in vivo.

Hexose-modified anti-viral analogues of uridine 5′-disphosphate glucose derivatives

Abstract A series of analogues of the anti-viral 5′- O -[[[[(tetrabenzyl-, or tetrabenzoyl-α- d -glucopyranosyl)oxy]-carbonyl]amino]sulfonyl]uridine, in which the α-glucose moiety has been replaced by α-mannose, or galactose, 2-acetamido-2-deoxy-α-glucopyranose, 2-deoxy-α-, and β-glucopyranose, 6-deoxy-α-, and β-glucopyranose and 2,4-dideoxy-α-glucopyranose, has been synthesized by reaction of the corresponding protected hexose having the 1-OH free with chlorosulfonyl isocyanate and 2′,3′- O -isopropylideneuridine. 5′- O -[[[[(2″,3″,4″,6″-Tetra- O -benzoyl-α- d -mannopyranosyl)oxy]carbonyl]- amino]sulfonyl]-2′,3′- O -isopropylideneuridine( 13 ), 5′- O -[[[[(2″,3″,4″,6″-tetra- O -benzoyl- and 2″,3″,4″,6″-tetra- O -benzyl-α- d -galactopyranosyl)oxy]carbonyl]amino]sulfonyl]-2′,3′- O -isopropylideneuridine ( 18 and 19 ), 5′- O -[[[[(2″-acetamido-2″-deoxy-3″,4″,6″-tri- O -benzoyl- and 3″,4″,6″-tri- O -benzoyl-2″-deoxy-α- d -glucopyranosyl)oxy]carbonyl]amino]sulfonyl]-2′,-3′- O -isopropylideneuridine ( 20 and 21 ) and the deisopropylidenated derivatives of 13 and 21 , showed anti-viral activity similar to that of the corresponding glucose analogues as determined by the inhibition of the cytopathic effect induced by HSV-1 replication.

Mode of action of a new type of UDP-glucose analog against herpesvirus replication.

The mode of action of a new type of UDP-glucose analog against herpes simplex virus type 1 (HSV-1) replication was examined. The analog showed good selectivity and potent activity. At 10 micrograms/ml, P-536 inhibited the formation of infectious HSV-1 by more than 90%, whereas at 100 micrograms/ml it had no cytotoxic effects, as evidenced by phase-contrast microscopy. P-536 showed a wide spectrum of action and was active against HSV-1, adenovirus type 5, vaccinia virus, poliovirus type 1, encephalomyocarditis virus, vesicular stomatitis virus, influenza virus, and measles virus, irrespective of whether these viruses have lipidic envelopes or not. P-536 clearly inhibited protein glycosylation if added at the time when late viral proteins were being synthesized. Moreover, it also interfered with the synthesis of nucleic acids and the phosphorylation of nucleosides. If P-536 was present from the beginning of infection, HSV-1 replication was blocked at an early step and the infected cells continued to synthesize cellular proteins for long periods. Images

Analogues of Uridinediphosphatehexoses. A New Type of Protein Glycosylation Inhibitors That Show Antiviral Activity

Abstract A series of analogues of UDP-Glc and UDP-GlcNAc prepared by reaction of protected hexoses with ClSO2NCO and 2′3′-O-isopropylideneuridine, inhibited glycosylation of proteins in HSV-1 infected HeLa cells and were active against several enveloped viruses.