Richard Dahlbom

On the inhibitory power of some further pyrazole derivatives of horse liver alcohol dehydrogenase

Abstract We found in 1969 (1) that the inhibitory power of pyrazole on LADH was greatly increased by methyl substitution in the 4-position. In this paper we have studied the effect of increasing the size of this side chain. The inhbitory power was found to increase by a factor of two for each methyl group added in a normal side chain. Some other side chains were tested. Already the 4-butyl and 4-pentyl pyrazoles were so active that for the calculation of their true inhibition constants these had to be corrected for the concentration of the enzyme (0.0005 μN). To our knowledge this never happened before.

Chitinase and beta-N-Acetylglucosaminidase in the Digestive Juice of Helix pomatia.

A beta-N-acetylglucosaminidase from Helix pomatia digestive juice was separated and partly purified by gel chromatography. The optimal pH for the degradation of p-nitrophenyl-N-acetyl-beta-D-glucosaminide was 3.4. The molecular weight was around 160 000 and the pI = 4.95. In the same gel chromatography run two chitinase active peaks were also obtained. These chitinase active peaks were also obtained. These chitinases, with molecular weights around 26 000 and 13 000, had somewhat different pH activity curves with optima at 4.2 and 4.3. By isoelectric focusing the first peak with molecular weight around 26 000 was divided in two chitinase active regions with pI at 5.7 and 3.5. The second peak with molecular weight around 13 000 had a pI at 7.3.

STEREOCHEMICAL REQUIREMENTS FOR CENTRAL AND PERIPHERAL MUSCARINIC AND ANTIMUSCARINIC ACTIVITY OF SOME ACETYLENIC COMPOUNDS RELATED TO OXOTREMORINE

1 The enantiomers of some analogues of the central muscarinic agent, oxotremorine, were prepared and investigated for tremorogenic and tremorolytic activity in intact mice and for muscarinic and antimuscarinic activity on the isolated ileum of the guinea‐pig. 2 The R‐isomers were more potent than the S‐isomers both in vivo and in vitro regardless of whether the compounds are agonists, partial agonists or competitive antagonists. 3 It is suggested that in the oxotremorine series, agonists and antagonists interact with a common receptor site, in contrast to classical muscarinic antagonists which are believed to bind also to accessory receptor areas, located close to the agonist binding site.

The pharmacological assessment of a new, potent oxotremorine analogue in mice and rats

Some of the central and peripheral effects of oxotremorine (OT) and its azetidine analogue, N-[4-azetidinyl)-2-butynyl]-2-pyrrolidone (BM 120), were compared in mice and rats. BM 120 was found to be about twice as potent as OT and to have a somewhat longer duration of action. All its effects were antagonized by pretreatment with atropine sulphate. BM 120 acted as powerful muscarinic agonist on the isolated guinea pig ileum.

Synthesis and pharmacological properties of N-[4-(1-azetidinyl)-2- butynyl]-2-pyrrolidone, a highly potent oxotremorine-like agent

Griffith, 0. R., Marshall, J., Nasmyth, P. A. (1978) Moncada, S., Bunting, S . , Mullane, K., Thorogood, Ibid. 64: 416P P., Vane, J. R., Raz, A,, IYeedleman, P. (1977) Hoffman, B. B., DeLean, A,, Wood, C. L., Schocken, D. D., Lefkowitz, R. J. (1979) Life Sci. 24: 1739-1746 Pearce, P. H., Wright, J. M., Egan, C. M., Scrutton, Hsu, C. Y . , Knapp, D. A,, Halushka, P. V. (1979) J. Pharmacol. Exp. Ther. 208: 366-375 Prostaglandins 13: 611-618

Stereoselectivity of some oxotremorine antagonists containing two chiral centres.

The stereoisomers of some analogues of oxotremorine containing two chiral centres, one in the 1‐position of the butynyl chain and one in the 2‐position of the pyrrolidine ring, have been prepared. The compounds are oxotremorine antagonists. They show a marked stereoselectivity, which depends mainly on the configuration of the chiral centre in the butynyl chain and to a lesser extent on the configuration of that in the pyrrolidine ring.

N-(t-Aminoalkynyl)-substituted pyrrolidones as oxotremorine antagonists

Eine Anzahl von Antagonisten zu Oxotremorin wurden durch kleine Modifikationen der Struktur des Oxotremorins erhalten. Die aktivste Verbindung, N-(1-Methyl-4-pyrrolidino-2-butinyl)pyrrolidon, ist mehr als sechsmal wirksamer als Atropin und hat eine grössere Spezifizität mit Bezug auf das Zentralnervensystem.

Muscarinic activity of some secondary and tertiary amines and quaternary ammonium salts structurally related to oxotremorine

A number of secondary and tertiary amines as well as quaternary ammonium compounds, obtained by structural modification of the amino group of oxotremorine (1) and its acetamide analogue (14), were investigated for muscarinic and antimuscarinic activity in vivo and in vitro. For the quaternary ammonium analogues, decrease of in vitro muscarinic potency is well correlated with increase of the size of the quaternary ammonium group, as estimated from increments in apparent molal volumes. A similar decrease of muscarinic potency with increasing substitution at the nitrogen atom is generally observed for the secondary and tertiary amines. For the latter the reduction in muscarinic activity appears to be due to loss of efficacy, since the higher homologues are partial agonists or antagonists. There is a highly significant correlation between muscarinic activity in vitro and central tremorogenic activity of the tertiary amines.

Stereospecificity of oxotremorine antagonists

Die optischen Antipoden der 3 sehr wirksamen Oxotremorinantagonisten, N-(1-Methyl-4-pyrrolidino-2-butinyl)pyrrolidon, N-(1-Methyl-4-pyrrolidino-2-butinyl)succinimid und N-(1-Methyl-4-perhydroazepino-2-butinyl)succinimid, sind hergestellt und auf ihre pharmakologische Aktivität geprüft worden: Die (+)-Antipoden, die R-Konfiguration haben, wurden als Träger der Aktivität erkannt, während die (−)-Antipoden praktisch unwirksam sind.

Muscarinic activity in the isolated guinea pig ileum of some carboxamides related to oxotremorine

A series of structural analogues of the potent oxotremorine-like agent N-(4-pyrrolidino-2-butynyl)-N-methyl-acetamide (1) was investigated for muscarinic activity in the isolated guinea pig ileum. Substitution of larger alkyl groups for the acetyl methyl group of 1 results in an attenuation of muscarinic potency. The observation that the agonist N-(4-dimethylamino-2-butynyl)-N-methylpropionamide (6) has a dissociation constant (KA = 5.1 X 10(-5) M), estimated after elimination of spare receptors with dibenamine, similar to that of the antagonist N-(4-dimethylamino-2-butynyl)-N-methyl-2,2-dimethylpropionamide (11) suggests that the decrease in muscarinic agonist activity with increasing substitution is due mainly to a loss of efficacy. The N-methyl group of 1 is essential for muscarinic activity since its replacement by a hydrogen atom or an ethyl group yields antagonists.