Piperazinylpyrazines with central serotoninmimetic activity.

A series of 2-(1-piperazinyl)pyrazines was synthesized and evaluated for central serotonin-like activity. The most interesting member of the series, 6-chloro-2(1-piperazinyl)pyrazine (3a), had pharmacological properties characteristic of potent central serotoninmimetic activity and only weak peripheral serotoninmimetic action. Structural similarities between 3a and serotonin are discussed.

2-Mercaptoacetamidines as gastric antisecretory agents.

A series of N-substituted 2-mercaptoacetamidines was synthesized and evaluated for gastric antisecretory activity in dogs stimulated with gastrin tetrapeptide. The most potent analogues showed 80--95% inhibition of acid secretion after an oral dose of 8 mg/kg. Thus, these compounds represent a new structural type having significant antisecretory activity. Disulfides had essentially the same antisecretory potency as the corresponding mercaptoacetamidines, indicating a metabolic interconversion. Alkylation of the mercapto group decreased potency. Higher carboxamidine homologues such as 2- and 3-mercaptopropionamidines had very low activity. Hydroxyacetamidines and mercaptoacetamides also had low potency. Side effects observed with this series of compounds included emesis, tachycardia, and gastric bleeding.

A deuterium isotope effect on the inhibition of gastric secretion by N,N-dimethyl-N'-[2-(diisopropylamino)ethyl]-N'-(4,6-dimethyl-2-pyridyl)urea. Synthesis of metabolites.

The use of isotopic substitution to retard the oxidative metabolism of the gastric antisecretory agent N,N-dimethyl-N'-[2-(diisopropylamino)ethyl]-N'-(4,6-dimethyl-2-pyridyl)urea (1) and improve its antisecretory potency was examined. The pyridine ring methyl hydrogens of 1 were replaced with either deuterium or fluorine. The hexadeuterated analogue (12) was found to be approximately 2.1 times more potent than the protio form (1) as an inhibitor of gastric acid secretion stimulated by gastrin tetrapeptide. The hexafluoro analogue (11) was 0.4 times as potent as 1. A useful pyridine ring synthesis was developed to prepare the metabolites of 1, 10a (4-hydroxymethyl) and 10b (6-hydroxymethyl), and the hexafluoro analogue 11. These syntheses involved the condensation of 1,3-diketones with an appropriately N-substituted amidinoacetate.

Conformational requirements for histamine H2-receptor inhibitors: a structure-activity study of phenylene analogues related to cimetidine and tiotidine.

Two series of compounds related to cimetidine and tiotidine were synthesized as part of a study to evaluate the importance of conformational parameters in binding at histamine H2 receptors. The flexible methylthioethyl connecting chain was replaced by a conformationally restricting phenylene unit. These compounds were evaluated for antagonism of the dimaprit-stimulated chronotropic response in the guinea pig atrium and inhibition of histamine stimulated secretion of gastric acid in the dog. In both series, biological activity is markedly dependent on the m-phenylene regioisomers. Histamine H2-receptor activity is retained in both series; however, in the tiotidine series, gastric antisecretory activity is significantly improved. Regardless of the end group, N-cyanoguanidine 1,1-diamino-2-nitroethene or 3,4-diamino-1,2,5-thiadiazole 1-oxide, each 3 3-(2-guanidino-4-thiazolyl)phenyl analogue was ca. 8 and 90 times more potent intravenously than tiotidine and cimetidine, respectively. The electronic influences of the phenylene unit on biological activity were also evaluated. It was concluded that the geometric constraints imposed by the m-phenylene connecting element were more important than electronic factors in binding events at the histamine H2 receptor.

Structure-activity, theoretical, and X-ray studies on the intramolecular interactions in a series of novel histamine H2 receptor antagonists.

The furan ring of the histamine H2 receptor antagonist 3-amino-4-[[2-[[[5-[(dimethylamino)methyl]-2-furanyl]-methyl] thio]ethyl]amino]-1,2,5-thiadiazole 1-oxide (1a) was replaced by thiophene, pyridine, benzene, and pyrrole. The relative receptor affinities of these analogues were estimated by in vitro and in vivo techniques. A theoretical model for the stacking interaction, observed by single crystal X-ray analysis of 1a, was developed, and the ability to enter into this type of interaction was estimated. The X-ray analysis of the pyridine analogue of 1a revealed no intramolecular stacking interaction. The theoretical studies were evaluated in light of the observed receptor affinities, and the relevance of the solid-state geometry of 1a to the receptor-bound geometry was assessed. It is suggested that the stacked geometry found in the X-ray structure of 1a does not represent a conformation that is relevant to that bound at the histamine H2 receptor.

Inhibitors of gastric acid secretion: antisecretory 2-pyridylurea derivatives.

A series of aminoalkyl-substituted pyridylureas has been prepared and evaluated as inhibitors of gastric acid secretion. N,N-Dimethyl-N'-[2-(diisopropylamino)ethyl]-N'-(4,6-dimethyl-2-pyridyl)urea (8g) was the most potent example of the class. Comparison of this compound with cimetidine showed it to be equipotent in dogs stimulated with gastrin tetrapeptide but approximately half as potent in dogs stimulated with histamine. Inhibition of secretion does not appear to result from antagonism of the histamine H2 receptor, since the compounds show only weak inhibition of the H2 receptor in vitro.

The anticonvulsant action of methazolamide in mice: antagonism by various inhibitors of dopamine beta-hydroxylase.

The dopamine beta-hydroxylase inhibitors, FLA-63 and picolinic acid, antagonized the anticonvulsant action of methazolamine in mice; disulfiram and pyrimidinethiol were inactive. FLA-63 and picolinic acid, but not disulfiram or pyrimidinethiol prevented pheniprazine restoration of the anticonvulsant action of methazolamide in reserpinized mice. The present findings clearly demonstrate that differences exist among inhibitors of dopamine beta-hydroxylase regarding their ability to antagonize the anticonvulsant action of methazolamide under various test conditions.

Subcutaneous administration of somatostatin analogs as a major factor in the enhancement of the duration of action.

Somatostatin and Des(Ala1Gly2)desaminol[Cys3]descarboxy-]Cys14[-]D-Trp8[dicarba3,14-somatostatin (Ia) are more potent inhibitors of glucagon, insulin and growth hormone release than the L-Trp8 analog (Ib). However when infused intravenously, these three compounds are equipotent but short-acting inhibitors of pentagastrin evoked gastric secretion in the dog. The duration of inhibition of equieffective antisecretory doses is significantly increased following subcutaneous administration 30 min prior to a food stimulus. The longest duration of antisecretory action is seen with the D-Trp8 analog (Ia) after subcutaneous administration.

Studies on MK-208 (YM-11170) a new, slowly dissociable H2-receptor antagonist.

MK-208 [3-(((2-(aminoiminomethyl)amino)-4-thiazolyl)-methyl)thio)-N'-(a minosulfonyl) propanimidamide], also known as YM-11170, is a highly potent histamine H2-receptor antagonist in guinea-pig atria, acting via a unique binding mechanism. Unlike ranitidine, the onset of action of this compound was slow and its inhibitory action was difficult to remove from the tissues by repeated washing. Preincubation of atria with ranitidine, however, protected the H2-receptor from these prolonged inhibitory effects of MK-208. The H2-receptor antagonism produced by MK-208 was not surmountable by increasing concentrations of dimaprit. The compound did not alter the response of this tissue to isoproterenol or affect basal atrial rate under conditions where maximal H2-receptor blockade was achieved. In dogs, MK-208 was effective in inhibiting gastric acid secretion evoked by histamine, gastrin and 2-deoxy-D-glucose. Orally, it was approximately 7 times as potent as ranitidine against histamine-induced secretion, and its duration of action was substantially longer. The compound was also highly effective in inhibiting basal acid secretion in chronic gastric fistula rats.