Improgan, a nonopioid antinociceptive agent, activates descending, pain-relieving mechanisms in the brain stem, but the receptor for this compound has not been identified. Because cannabinoids also activate nonopioid analgesia by a brain stem action, experiments were performed to assess the significance of cannabinoid mechanisms in improgan antinociception. The cannabinoid CB 1 antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A) induced dose-dependent inhibition of improgan antinociception on the tail-flick test after i.c.v. administration in rats. The same treatments yielded comparable inhibition of cannabinoid {R-(ϩ)-(2,3-dihydro-5-methyl-3-[(4-mor pholinyl)methyl]pyrol[1,2,3-de]-1,4-benzoxazin-6-yl)(1-naphthalenyl)methanone monomethanesulfonate, WIN 55,212-2} analgesia. Inhibition of improgan and WIN 55,212-2 antinociception by SR141716A was also observed in Swiss-Webster mice. Radioligand binding studies showed no appreciable affinity of improgan on rat brain, mouse brain, and human recombinant CB 1 receptors, ruling out a direct action at these sites. To test the hypothesis that CB 1 receptors indirectly participate in improgan signaling, the effects of improgan were assessed in mice with a null mutation of the CB 1 gene with and without SR141716A pretreatment. Surprisingly, improgan induced complete antinociception in both CB 1 (Ϫ/Ϫ) and wild-type control [CB 1 (ϩ/ϩ)] mice. Furthermore, SR141716A inhibited improgan antinociception in CB 1 (ϩ/ϩ) mice, but not in CB 1 (Ϫ/Ϫ) mice. Taken together, the results show that SR141716A reduces improgan antinociception, but neither cannabinoids nor CB 1 receptors seem to play an obligatory role in improgan signaling. Present and previous studies suggest that ⌬ 9 -tetrahydrocannabinol may act at both CB 1 and other receptors to relieve pain, but no evidence was found indicating that improgan uses either of these mechanisms. SR141716A will facilitate the study of improgan-like analgesics.

No abstract

No abstract

Growth of Penicillium charlesii G. Smith on a medium containing D -glucose gave an extracellular galactan and mannan. Selective hydrolysis of the galactan component with O-OlS~-sulphuric acid led to the isolation of the mannan. It was electrophoretically homogeneous and contained eight D-mannopyranosyl units. Hydrolysis of the methylated mannan gave 2,3,4,6-tetra-O-methyl-~-mannose (2 parts), 3,4, 6-tri-O-methyl-~-mannose (5 parts), and 3,4-di-O-methyl-~-mannose (1 part). Hence the mannose units are joined together by 1,2-linkages, with a branching point at C(s) of one of these units. Periodate oxidation confirmed these structural features and suggested that there are four D-mannopyranosyl units on either side of the 1,6-linkage, as in (I).PERIODATE oxidation methods li2 have been developed for investigating, on a semimicroscale, the interglycosidic units present in oligosaccharides, with a view to their subsequent application to polysaccharides, in particular those isolated in small yield by microbiological procedures. These methods have now been applied, in conjunction with the methylation method, to the mannan3 of low molecular weight produced in the culture medium of

: Sweetness magnification of sucrose occurs when specific hydroxyls are replaced with chloro groups, particularly at carbons 4, l', 4' and 6, but not 6, rising progressively from 2 -20 times in mono-chlorides to >5000 times in tetrachlorides. This surge in activity is interpreted by the formation of a sweetenerreceptorcomplex, loosely linked by two H-bonds from 2-0 (B, ) and 3'-OH (AH,) of the sucrose derivative to the N-asparaginyl unit of an a-helical protein, which is strengthened by dispersive interactions with the side-chains of the receptor protein.These interactions increase in proportion with the degree of chloro-substitution in the sweet compounds, as illustrated by the molecular modelling by computer graphics.,The sweetness of sucrose (1, R=R,=OH), the conventional standard (lx), can be manipulated 'upwards or downwards in a variety of ways by using either additives or structural changes. Thus, caramel-type molecules, such as maltol or furaneol, enhance its sweetness by 10 -20% (ref. 1) andso does synergism with H, I. sweeteners, especially aspartame, cyclamate, acesulphame and saccharin.Also, replacement of certain hydroxyl groups in sucrose by chloro groups can either enhance or r reduce its sweet taste, the 6-mono-chloride (1, R=CI, R,=OH) being virtually tasteless whilst the 6-mono-chloride (1, R=OH, R,=C1) is 20x sweeter (ref.2). The presence of arylalkanoic acids, such asp -methoxyphenylpropanoic acid, can dramatically reduce the sweetness of sucrose by up to 80%. An understanding of these phenomena requires an initial knowledge of the prosthetic hydroxyls in sucrose that trigger the response, the nature of the taste receptor and its active site, and the mechanism of the interaction with the receptor.In common with most sweet sugars and polyols, sucrose (1) utilises two of its hydroxyls to act as hydrophilic AH, I B, glucophore, where A and B are electronegative atoms separated by only 2.5 -4.0 A and in this case oxygen, which can interact with a similar AH, / B, unit on the proteinaceous receptor., In this way a sweetener-receptor complex is formed, joined by two intramolecular H-bonds (2) as suggested by Shallenberger and A m (ref.3), which allows gauche or staggered a,P-diols to be sweet but not antiperiplaner or eclipsed groups; on a pyranose chair conformation, di-equatorial or equatorial-axial diols are permitted but not trans-diaxial diols. Taste studies on counterparts of each wing of sucrose, namely the slightly sweet methyl a-D-glucopyranoside (0.1~) and the unsweet methyl P-Dfructofuranoside suggested an unusual AH,/ B, unit arising from one hydroxyl on the glucosyl unit and the other on the fructosyl unit (ref. 2). As a further complication, there are two major conformations of sucrose (1, R=R,=OH) in solution, each with an intramolecular H-bond, one between the 1'-OH and 2-0 (3), and the other from 3'-OH to 2-0 (4), with the former predominating in the ratio of 2 : 1 (ref. 4). On the above evidence only these pairs of closely placed hydroxyls, at 693