1 The 5-HT4 receptor has only recently been identified but has yet to be cloned. This paper describes the pharmacology of a potent and selective 5-HT4 receptor antagonist, GR113808, which will be useful in the further characterization of this receptor. 2 On the guinea-pig ascending colon, GRI 13808 (1 nM-0.1 M) behaved as an antagonist of 5-hydroxytryptamine (5-HT)-induced contraction, producing rightward displacements of the concentration-effect curve to 5-HT and a concentration-related depression of the maximum effect. However, the compound had no effect on cholecystokinin (CCK-8)-induced contraction in concentrations up to 1 LM. 3 In the guinea-pig colon preparation, onset and offset of the antagonism by GRI13808 of 5-HTinduced contraction was examined. Incubation of the tissues for either 15 min, 30 min or 60 min produced similar rightward displacements of the concentration-effect curves to 5-HT, with no increase in the degree of depression of the maxima with increasing time of incubation. Experiments examining offset of antagonism (0.01 4M) demonstrated that washout for 30 min was required to reverse fully the effects of the antagonist. 4 Potency estimates in the colon for GRI13808 were made by determining approximate pA2 values (30 min) using the Gaddum equation. The values obtained were 9.2, 9.7 and 9.2 when tested against the agonists 5-HT, 5-methoxytryptamine and R,S-zacopride respectively. 5 On the carbachol-contracted tunica muscularis mucosae preparation of the rat thoracic oesophagus, GR 113808 behaved as an antagonist of 5-HT-induced relaxation, producing no reduction in maximum response. Analysis of these data yielded a pA2 of 9.3. GR1 13808 also antagonised the relaxant effects of 5-methoxytryptamine (pA2 = 9.0) and R,S-zacopride (pA2 = 9.4). The compound had no effect on isoprenaline-induced relaxation of the carbachol-contracted oesophagus at a concentration of 1 gM.6 In tests of selectivity, GR113808 had only low affinity for 5-HT3 receptors (pKi = 6.0) and had no functional activity at either 5-HT2 or 5-HT,-like receptors on vascular smooth muscle preparations. In a range of binding assays, GRi 13808 was shown to have no appreciable affinity for any other receptor type investigated. 7 In the anaesthetized piglet, GRI13808 was a potent antagonist of 5-methoxytryptamine-induced tachycardia (mean DRo = 97.2 gg kg-' h-'). The compound was ineffective against isoprenaline-induced tachycardia. 8 The present results are discussed in comparison with those for existing antagonists at the 5-HT4 receptor. The results of this study indicate that GRI13808 will be a valuable antagonist for studying 5-HT4 receptor mechanisms in vitro and in vivo and validate its use as a radioligand for determining 5-HT4 receptor distribution.
Proxiphomin (I ), a naturally occurring [I 3]cytochalasan, has been synthesized by a route which uses an intramolecular Diels-Alder reaction of the long chain 3 -( I -oxotrienyl)pyrrol-2(5H) -one (1 8) to form the 13-membered ring. This cyclization gave a mixture of endo and exo isomers (19) and (21), the endo isomer (1 9) being carried through t o proxiphomin. Although the endo-exo selectivity was small, (1 9) : (21 ) = 52: 48, the Diels-Alder cyclization was useful in that n o epimerization had occurred at C-5. Cyclization of a mixture of Diels-Alder precursors (1 8) and (33) prepared from racemic pyrrolidinone (32) gave all four cyclized products (19), ( 21), (34), and (36) which were 1-debenzoylated, separated, and characterized.
3-(3-Cyclopentyloxy-4-methoxy-benzyl)-8-isopropyl-adenine V11294 (1) has been identified as a lead structure, which selectively inhibits human lung PDE4 (436 nM) and is also active in a number of in vitro and in vivo models of inflammation. Here we describe the synthesis and pharmacology of a series of highly potent 8-[(benzyloxy)methyl]-substituted analogues, with potencies in the range 10-300 nM. In addition, several compounds showed interesting PDE4 subtype specificities, for example, the 3-thienyl derivative 5v, which showed 6-10 nM potency at PDE4B, D3, and D5 and a 20- to 200-fold selectivity over A and D2, respectively.
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