5-Amino-6-chloro-N-[(1-isobutylpiperidin-4-yl)methyl]-2-methylimidazo[1,2-alpha]pyridine-8-carboxamide (CJ-033,466), a novel and selective 5-hydroxytryptamine4 receptor partial agonist: pharmacological profile in vitro and gastroprokinetic effect in conscious dogs.

5-Hydroxytryptamine (5-HT) receptors and dopamine(2) (D(2)) receptor modulate gastrointestinal motility. Gastroprokinetic agents that act on several 5-HT receptor subtypes and/or D(2) receptors are used clinically. Although the 5-HT(4) receptor is known to mediate the gastroprokinetic effects of these agents, the absence of highly selective 5-HT(4) receptor agonists has made it difficult to confirm the physiological consequences of selective 5-HT(4) receptor stimulation. In this study, we report the in vitro pharmacological profiles and the in vivo gastroprokinetic effects of 5-amino-6-chloro-N-[(1-isobutylpiperidin-4-yl)methyl]-2-methylimidazo[1,2-alpha]pyridine-8-carboxamide (CJ-033,466), a novel, potent, and selective 5-HT(4) partial agonist. Compared with preceding 5-HT(4) agonists such as cisapride, mosapride, and tegaserod, CJ-033,466 had a superior in vitro profile, with nanomolar agonistic activities for the 5-HT(4) receptor and 1000-fold greater selectivity for the 5-HT(4) receptor over other 5-HT and D(2) receptors. In vivo studies in conscious dogs showed that CJ-033,466 dose-dependently stimulated gastric antral motility in both the fasted and postprandial states at the same dose range and that it was 30 times more potent than cisapride. Furthermore, CJ-033,466 accelerated the gastric emptying rate in a gastroparesis dog model at the minimally effective dose established in the gastric motility study. In conclusion, CJ-033,466 is a potent and highly selective 5-HT(4) agonist that stimulates physiologically coordinated gastric motility, and it has no activity on other 5-HT receptor subtypes and D(2) receptors. Therefore, CJ-033,466 could be used to treat gastroparesis, providing better gastroprokinetics and reduced side effects mediated by the other receptors.

Pharmacological properties of a novel nociceptin/orphanin FQ receptor agonist, 2-(3,5-dimethylpiperazin-1-yl)-1-[1-(1-methylcyclooctyl)piperidin-4-yl]-1H-benzimidazole, with anxiolytic potential.

We have characterized the pharmacological properties of the novel nociceptin/orphanin FQ peptide receptor (NOP receptor) agonist, 2-(3,5-dimethylpiperazin-1-yl)-1-[1-(1-methylcyclooctyl)piperidin-4-yl]-1H-benzimidazole (PCPB). PCPB bound to the NOP receptor in mouse brain membranes (Ki=0.12 nM) and to recombinant human NOP receptor (Ki=2.1 nM). PCPB showed full agonism for the NOP receptor in isolated mouse vas deferens with a maximal effect and high potency that were similar to the pharmacological profile observed for nociceptin/orphanin FQ (N/OFQ) (pD(2): 6.9+/-0.2; 95+/-2% activity). Orally administered PCPB (30 mg/kg) penetrated well into the brains of the mice. PCPB exhibited an anxiolytic activity in mice subjected to the Vogel conflict test that was comparable to the maximal response induced by diazepam, a representative anxiolytic agent. The anxiolytic effect of PCPB was dose-dependently blocked by the NOP receptor antagonist, J-113397, demonstrating that this effect was mediated by the NOP receptor agonist activity. Behavioral studies in mice also showed that PCPB prolonged the pentobarbital-induced sleeping time but did not cause muscle relaxation at the oral anxiolytic dose of 30 mg/kg. Unlike diazepam, however, these central effects of PCPB were weak. Our results indicate that PCPB is a potent anxiolytic agent with agonistic activities for the NOP receptor.

A novel antibiotic CJ-17,572 from a fungus, Pezicula sp.

A new antibiotic, CJ-17,572 (I) was isolated from the fermentation broth of a fungus Pezicula sp. CL11877. The structure of I was determined to be a new equisetin derivative by spectroscopic analyses. The compound inhibits the growth of multi-drug resistant Staphylococcus aureus and Enterococcusfaecalis with IC50s of 10 and 20 microg/ml, respectively.

CJ-21,058, a new SecA inhibitor isolated from a fungus.

A new equisetin derivative, CJ-21,058 (I) was isolated from the fermentation broth of an unidentified fungus CL47745. It shows antibacterial activity against Gram-positive multi-drug resistant bacteria by inhibiting ATP-dependent translocation of precursor proteins across a bacterial cell membrane.

CJ-15,696 and its analogs, new furopyridine antibiotics from the fungus Cladobotryum varium: fermentation, isolation, structural elucidation, biotransformation and antibacterial activities.

CJ-15,696 and 7 novel furopyridine antibiotics were isolated from the fungus Cladobotryum varium CL12284. Their structures were determined by X-ray crystallography and spectral analysis. Three biotransformed analogs were also prepared from CJ-15,696. CJ-15,696 showed moderate activity against various Gram-positive bacteria including some drug resistant strains such as methicillin resistant Staphylococcus aureus (MRSA).

Pharmacological evaluation of a novel cannabinoid 2 (CB2) ligand, PF-03550096, in vitro and in vivo by using a rat model of visceral hypersensitivity.

Previous studies have shown that cannabinoid 2 (CB(2))-receptor agonists might have analgesic effects on visceral hypersensitivity. To extend these results, we have determined the pharmacological characteristics of a newly designed CB(2) ligand, N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(3-hydroxy-3-methylbutyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide (PF-03550096), in vitro and in vivo. PF-03550096 showed high affinity to human (K(i) = 7.9 +/- 1.7 nM) and rat CB(2) receptors (K(i) = 47 +/- 5.6 nM). In a cell-based functional assay, PF-03550096 behaved as a full agonist and showed high selectivity for human CB(2) receptors. Orally administered PF-03550096 (3, 10 mg/kg) inhibited the 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced decrease in colonic pain threshold with statistical significance. The inhibitory effect of PF-03550096 (10 mg/kg) was significantly reversed by a selective CB(2) antagonist, N-(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl-5-(4-chloro-3-methylphenyl)-1(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528), while SR144528 itself did not modify colonic pain threshold. These results indicate that PF-03550096 is a potent CB(2) agonist and possesses efficacy in a rat model of visceral hypersensitivity.

Pharmacological characterization of the newly synthesized nociceptin/orphanin FQ-receptor agonist 1-[1-(1-methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole as an anxiolytic agent.

Nociceptin/orphanin FQ peptide (NOP)-receptor agonists have been shown to produce anxiolytic-like effects in rodents subjected to various behavioral assays. Recently, we developed a new nonpeptide agonist of the NOP receptor, 1-[1-(1-methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole (MCOPPB), as an anxiolytic agent. MCOPPB has a high affinity for the human NOP receptor (pKi = 10.07 +/- 0.01) and selectivity for the NOP receptor over other members of the opioid receptor family: 12-, 270- and >1000-fold more selective for the NOP receptor than for the micro-, kappa-, and delta-receptor, respectively. In an ex vivo binding study, MCOPPB (10 mg/kg, p.o.) inhibited signaling through the NOP receptor in the mouse brain, suggesting that it penetrated into the brain after it was orally administered. In the mouse Vogel conflict test, MCOPPB (10 mg/kg, p.o.) and diazepam (3 mg/kg, p.o.) elicited anxiolytic-like effects, although MCOPPB produced a bell-shaped response curve. In addition, MCOPPB (10 mg/kg, p.o.) was still effective as an anxiolytic agent even after repeated administration for 5 days. MCOPPB at an oral dose of 10 mg/kg did not affect locomotor activity or memory, nor did it contribute to ethanol-induced hypnosis. On the other hand, the benzodiazepine-type anxiolytic agent diazepam caused memory deficits and enhanced ethanol-induced hypnosis. These findings suggest that MCOPPB - a compound with few adverse effects on the central nervous system - is a potential therapeutic agent for the treatment of anxiety.