Raymond Baker

Tachykinin NK1 receptor antagonists act centrally to inhibit emesis induced by the chemotherapeutic agent cisplatin in ferrets

These studies have compared the pharmacological profile of two non-peptide human type neurokinin1 (hNK1) receptor selective antagonists, L-741,671 and a quaternised compound L-743,310. In radioligand binding studies L-741,671 and L-743,310 had high affinity for ferret and cloned hNK1 receptors [Ki (nM) ferret 0.7 and 0.1; human 0.03 and 0.06, respectively] but low affinity for rodent NK1 receptors [Ki (nM) 64 and 17, respectively] suggesting that ferret receptors have hNK1-like binding pharmacology. Studies in vivo showed that L-741,671 and L-743,310 had equivalent functional activity in the periphery (ID50s of 1.6 and 2 micrograms/kg i.v., respectively) as measured by inhibition of plasma protein extravasation evoked in the oesophagus of guinea pigs by resiniferatoxin (7 nmol/kg i.v.). Using an in situ brain perfusion technique in anaesthetised rats, L-741,671 was shown to be much more brain penetrant than the quaternary compound L-743,310 which had an entry rate similar to the poorly brain penetrant plasma marker inulin. These compounds thus provided an opportunity to compare the anti-emetic effects of equi-active hNK1 receptor antagonists with and without brain penetration to central NK1 receptor sites. When tested against cisplatin-induced emesis in ferrets, L-741,671 (0.3, 1 and 3 mg/kg i.v.) produced marked dose-dependent inhibition of retching and vomiting but L-743,310 was inactive at 3 and 10 micrograms/kg i.v. In contrast, direct central injection of L-741,671 and L-743,310 (30 micrograms) into the vicinity of the nucleus tractus solitarius or L-743,310 (200 micrograms) intracisternally was shown to inhibit retching and vomiting induced by i.v. cisplatin. L-741,671 and L-743,310 had equivalent functional activity, at the same dose, against cisplatin-induced emesis when injected centrally. These observations indicated that had L-743,310 penetrated into the brain after systemic administration it would have been active in the cisplatin-induced emesis assay and so show that brain penetration is essential for the anti-emetic action of systemically administered NK1 receptor antagonists.

The total synthesis of myo-inositol polyphosphates

Abstract Total synthesis of the individual enantiomers of myo-inositol 4-phosphate ( 15 ), myo-inositol 1,4-bisphosphate ( 2 ) and myo-inositol 1,4,5-trisphosphate ( 1 ), together with syntheses of racemic myo-inositol 1,3,4-trisphosphate ( 4 ) and myo-inositol 2,4,5-trisphosphate ( 5 ) are reported. The syntheses feature the use of camphanic acid esters for resolution of protected inositols, and the use of tetrabenzylpyrophosphate as an efficient phosphorylating agent for polyhydroxy alcohols.

Identification and synthesis of the major sex pheromone of the olive fly (Dacus oleae)

The major component of the sex pheromone of the olive fly has been shown to be 1,7-dioxaspiro[5.5] undecane (1) and its structure has been confirmed by unambiguous synthesis; field studies have confirmed its biological activity.

Isolation and identification of the sex pheromone of the mediterranean fruit fly, Ceratitis capitata(Wied)

The volatile compounds emitted by sexually mature male mediterranean fruit flies (Ceratitis capitata) have been identified and the key component involved in the sexual attraction of virgin female flies to males demonstrated to be the novel sex pheromone 3,4-dihydro-2H-pyrrole (1).

The synthesis of (+)- and (–)-epibatidine

The synthesis of the alkaloid epibatidine {exo-2-(2-chloro-5-pyridyl)-7-azabicyclo[2.2.1]heptane} in enantiomeric form involving, as the critical step, reaction or 5-lithio-2-chloropyridine with N-tert-butoxycarbonyl-7-azabicyclo[2.2.1]heptan-2-one is described.

The design of novel muscarinic partial agonists that have functional selectivity in pharmacological preparations in vitro and reduced side-effect profile in vivo

Antagonist/agonist binding ratios (NMS/Oxo-M ratio) were used as an index of the efficacy of novel compounds acting at muscarinic receptors. These binding ratios have been used with a range of functional pharmacological assays to investigate the effects of varying the efficacy of muscarinic agonists. This strategy has been used as a means of obtaining functional receptor selectivity by exploiting differences in effective receptor reserves. The oxadiazole and pyrazine muscarinic agonists L-670,548 (NMS/Oxo-M ratio 1100) and L-680,648 (NMS/Oxo-M ratio 690) are amongst some of the most potent and efficacious agonists known. Decreasing the efficacy of compounds from these series, resulted in compounds with functional selectivity. The chloropyrazine L-689,660 (NMS/Oxo-M ratio 28) was an agonist on the rat superior cervical ganglion (M1), a partial agonist on the guinea-pig ileum (M3), but was an antagonist in the guinea-pig atria (M2). Synthesis of compounds with even lower predicted efficacy, such as the cyclopropyloxadiazole L-687,306 (NMS/Oxo-M ratio 15), maintained agonist activity in the ganglion, but showed antagonist activity in the M3 ileal, as well as the M2 atrial preparations. When tested in vivo these compounds did not produce many of the side effects associated with more efficacious agonists, particularly those associated with the cardiovascular system. However, they were active in reversing scopolamine-induced deficits in a variety of behavioural paradigms. This approach shows how functional selectivity for muscarinic receptor subtypes can be achieved in vitro, that in vivo reduces the dose-limiting side effects normally associated with muscarinic agonists.

Identification and synthesis of (Z)-(1′S,3′R,4′S)(–)-2-(3′,4′-epoxy-4′-methylcyclohexyl)-6-methylhepta-2,5-diene, the sex pheromone of the southern green stinkbug, Nezara viridula(L.)

The sex pheromone of the male green stinkbug, Nezara viridula(L.) has been shown to be a novel epoxybisabolene (Z)-(1′S,3′R,4′S)(–)-2-(3′,4′-epoxy-4′-methylcyclohexyl)-6-methylhepta-2,5-diene, whose structure has been confirmed by spectroscopic studies and synthesis of the eight possible stereoisomers.

Chemical composition of the frontal gland secretion ofSyntermes soldiers (Isoptera, Termitidae)

The defensive secretions from the frontal glands of soldier termites of the genusSyntermes contain similar mixtures of mono- and sesquiterpene hydrocarbons. The major components inS. dirus, S.molestus, S. brevimalatus, S. peruanus, and a new species (Syntermes sp. n), iscis-β-ocimene. A substantial amount of aristolochene is found inSyntermes sp. n. and is present at lower levels in all the other species;S.brevimalatus contains onlycis-β-ocimene and aristolochene. The four other species also contain minor amounts of epi-α-selinene and germacrene A. The latter compound has been identified on the basis of its rearrangement product β-elemene. The termiteS. grandis differed markedly from the otherSyntermes species in that no terpenoid components were found in the soldier extract. With the obvious exception ofS. grandis, the same soldier-specific mono- and sesquiterpenes occurred in all species. The total amount of secretion per unit weight of soldiers varies with the species and is inversely proportional to the development of the mandibular apparatus. InS.molestus smaller gland size is compensated for by a greater number of soldiers foraging trails.

A novel series of non‐quaternary oxadiazoles acting as full agonists at muscarinic receptors

1 A novel series of non‐quaternary oxadiazole‐based muscarinic agonists demonstrated high affinity for muscarinic receptors. 2 These agonists possessed high efficacy in the nanomolar range at muscarinic receptors in the superior cervical ganglion, atrium and ileum but did not show selectivity across the tissue preparations. 3 Two amino oxadiazoles, one from a quinuclidine series (L‐660,863) and one from a 1‐azanorbornane series (L‐670,207) possessed a high ratio of potency for displacing the binding of [3H]‐N‐methylscopolamine ([3H]‐NMS) to potency for displacing the agonist [3H]‐oxotremorine‐M ([3H]‐oxo‐M) (NMS/oxo‐M ratio) predictive of high efficacy in the cortex. 4 The two azanorbornane derivatives L‐670,548 and L‐670,207 stimulated the turnover of phosphatidylinositol in the cortex with a potency higher than that obtained with any other known muscarinic agonist (ED50 0.26 and 0.18 μm respectively). 5 The maximum response obtained with L‐670,207 was greater than that observed for carbachol but was comparable to that of the natural ligand acetylcholine. 6 These oxadiazole muscarinic agonists are among the most potent and efficacious non‐quaternary muscarinic agonists ever described.

Amino acid bioisosteres: design of 2-quinolone derivatives as glycine-site N-methyl-D-aspartate receptor antagonists

Abstract 3-Substituted-2-quinoloners ( 6–8 ) have been identified as glycine-site N-methyl-D-aspartate receptor antagonists. It is proposed that the α-phenyl lactam unit in the potent 4-hydroxy-3-phenyl derivatives ( 7d and 8b , L-701,315) may act as a glycine bioisostere in receptor recognition.