Yoshinari Satoh

Novel potent antagonists of human neuropeptide Y-Y5 receptor. Part 4: tetrahydrodiazabenzazulene derivatives

Novel tetrahydrodiazabenzazulene derivatives, designed from the lead compound 1 discovered by screening of our in-house chemical library, were prepared and found to be potent neuropeptide Y-Y5 (NPY-Y5) receptor antagonists. The structure-activity relationships are described. Compounds 7 (FR240662) and 16 (FR252384) were especially attractive owing to their high affinities for the NPY-Y5 receptors, oral absorption and permeability to brain.

Novel potent antagonists of human neuropeptide Y Y5 receptor. Part 1: 2-Oxobenzothiazolin-3-acetic acid derivatives

Novel NPY-Y5 antagonist FR73966 was discovered by screening of our in-house chemical library. The analogues were prepared by application of parallel synthesis techniques. Some of the resulting 2-oxobenzothiazolin-3-acetic acid derivatives exhibited nanomolar binding affinity for human NPY-Y5 receptors.

Novel potent antagonists of human neuropeptide Y Y5 receptors. Part 3: 7-methoxy-1-hydroxy-1-substituted tetraline derivatives.

As a part of our continuing research on NPY-Y5 receptor antagonists in the series of novel 6-methoxybenzo[a]cycloheptene derivatives, we discovered a novel skeleton, 7-methoxy-1-hydroxytetraline 7 which had been used as an intermediate, to be more suitable for increasing potencies leading to compound 3 (FR230481). Additionally, we discovered that the naphthalenesulfonamide moiety which was thought to be an essential pharmacophore could be replaced by the 5-chlorobenzothiazolin-3-acetic acid moiety to lead to potent compound 4 (FR233118). The structure-activity relationships on compounds 3,4 and their related derivatives are described. Unfortunately, although compounds 3 and 4 had very high affinities for Y5 receptors, their poor permeabilities to brain were shown by exo-vivo binding assays when orally administered.

Novel potent antagonists of human neuropeptide Y Y5 receptors. Part 2: substituted benzo[a]cycloheptene derivatives

Novel benzo[a]cycloheptene derivatives were prepared for the purpose of searching new neuropeptide Y-Y5 (NPY-Y5) receptor antagonists. The structure-activity relationships are described and compound 2o (FR226928) showed the most potent affinity for Y5 receptor of all we prepared and was found to have higher potency and better selectivity for Y5 over Y1 receptor affinities when compared with the known lead compound 1.

Studies on the syntheses of heterocyclic compounds. Part 679. A stereoselective total synthesis of (±)-ophiocarpine; a simple route to 13-hydroxyberbines

Phenolic cyclisation of (1R*)-1-[(α,R*)-α,3-dihydroxy-4-methoxybenzyl]-1,2,3,4-tetrahydro-6,7-methylenedioxy-isoquinoline (21) gave 10-methoxy-2,3-methylenedioxy-13aα-berbine-9,13β-diol (33) and the isomeric 11,13β-diol (34). 9-O-Methylation of the diol (33) gave (±)-ophiocarpine (3). A general synthesis of 13-hydroxy-berbines from 1,2,3,4-tetrahydro-α-hydroxybenzylisoquinolines by Mannich reaction and phenolic cyclisation is described.

Studies on the syntheses of heterocyclic compounds—DXXII : Photolytic synthesis of 1,12-dihydroxy-2,10,11- trimethoxyhomoaporphine

Abstract Photolysis of 1-(2-bromo-3-hydroxy-4,5-(dimethoxyphenethyl)-1,2,3,4-tetrahydro-7-hydroxy-6-methoxy-2-methylisoquinoline ( 8 ) gave 4,5,6,6a-tetrahydro-1,12-dihydroxy-2,10,11-trimethoxy-6-methylhomoaporphine ( 7 ), which is identical with the alkaloid CC-24 isolated from Cholchicum cornigerum .

Dual CCK-A and -B receptor antagonists (I) C9-methyl-1,4-benzodiazepines

Abstract A novel series of potent CCK-A and CCK-B dual antagonists has been prepared which incorporate a methyl substituent at the 9 position of a 1,4-benzodiazepine ring system. FR193108 ((+)- 11 ) was selected for further biological evaluation, and is expected to be more efficacious than CCK-A selective antagonists for the treatment of pancreatitis, since it has high and well-balanced affinities for both CCK-A and -B receptors.

Augmentation of the inhibitory effect of FK480, a CCK-A receptor antagonist, on pancreatic exocrine secretion by achlorhydria

The effect of intraluminal acid and cholecystokinin (CCK) receptor blockade on the pancreatic secretory response was examined in rats. Blockade of gastric acid secretion by YM022 (CCK-B receptor antagonist) or famotidine (histamine-2 receptor antagonist) resulted in a significant suppression of casein-stimulated pancreatic exocrine secretion as determined by juice volume and amylase secretion. Ligation of the gastric pylorus, which leads to complete prevention of gastric acid from entering the duodenum, also suppressed pancreatic exocrine secretion. FK480 (CCK-A receptor antagonist) inhibited pancreatic exocrine secretion dose dependently at doses of 0.01-1.0 mg/kg. When submaximal doses of FK480 and YM022 were treated concomitantly, pancreatic exocrine secretion was inhibited more profoundly than when treated solely. Hydrochloric acid (HCl; 0.05 N), injected into the duodenum, stimulated pancreatic exocrine secretion to a level comparable to that exhibited by intraduodenal casein. This effect of HCl was inhibited by FK480 (1.0 mg/kg) but not by YM022 (1.0 mg/kg). These findings suggest that inhibition of gastric acid secretion leads to the suppression of pancreatic exocrine secretion through mechanisms mediated by CCK-A receptors.

Effect of FK480, a CCK-A Receptor Antagonist, on Spontaneously Developed Chronic Pancreatitis in WBN/Kob Rats

The effect of FK480, a cholecystokinin-A (CCK-A) selective receptor antagonist, on spontaneously developed chronic pancreatitis was examined in WBN/Kob rats. Animals at age 18 weeks (18w-Control) already had the histologic appearance of chronic pancreatitis as indicated by inflammatory cell infiltration and fibrotic degeneration with interstitial edema. Rats treated with vehicle from 18 to 26 weeks of age (26w-Control) showed further development of pancreatitis as characterized by more extensive appearance of inflammatory cell infiltration and fibrotic changes, with the pancreatic weight significantly decreased. Serum amylase levels of 26w-Control animals were slightly decreased compared with those of 18w-Control animals, although the difference was not statistically significant. When rats were treated orally with 1, 10, and 100 μg/kg FK480 from 18 to 26 weeks of age, the decrease in serum amylase levels recovered dose dependently compared with 26w-Control, and the level in animals treated with 100 μg/kg FK480 was almost the same as that in 18w-Control rats. Histologic examinations revealed that the appearance of the pancreas of animals treated with FK480 was slightly improved with respect to inflammatory cell infiltration and edematous changes at the highest dose examined, although the difference was not statistically significant. Although blockade of the CCK-A receptor could be considered to exacerbate chronic pancreatitis due to possible inhibition of the trophic action of CCK, our results suggest that CCK-A receptor antagonists may not be detrimental to chronic pancreatitis.

Total syntheses of (–)-O-methylandrocymbine, (–)-kreysigine, and alkaloid CC-10 methyl ether

(–)-O-Methylandrocymbine (1) was obtained from (–)-1-(2-bromo-3,4,5-trimethoxyphenethyl)-1,2,3,4-tetrahydro-7-hydroxy-6-methoxy-2-methylisoquinoline (13a) by irradiation. The corresponding (+)-phenolic bromoisoquinoline (13b) gave alkaloid CC-10 methyl ether [(+)-O-methylandrocymbine](3) and (–)-kreysigine (6).