Ann G. Hayes

6,7-Dinitro-quinoxaline-2,3-dion and 6-nitro,7-cyano-quinoxaline-2,3-dion antagonise responses to NMDA in the rat spinal cord via an action at the strychnine-insensitive glycine receptor

6,7-Dinitro-quinoxaline-2,3-dion (DNQX) and 6-nitro,7-cyano-quinoxaline-2,3-dion (CNQX) produce an unsurmountable antagonism of responses to N-methyl-D-aspartate (NMDA) in the baby rat hemisected spinal cord. These effects of DNQX and CNQX can be prevented in a dose-dependent manner by co-superfusion with D-serine or glycine (in the presence of strychnine). The results suggest that the unsurmountable blockade of NMDA responses by DNQX and CNQX reflects an antagonist effect mediated at the allosterically linked strychnine-insensitive glycine receptor.

Novel 1, 2, 4-oxadiazoles as potent and selective histamine H3 receptor antagonists

Abstract Replacement of the isothiourea moiety of known histamine H 3 antagonists by certain 5-membered heteroaromatic systems can give compounds with an improved activity profile. One of these, 3-[(4-chlorophenyl)methyl]-5-[2-(1H-imidazol-4-yl)ethyl] 1,2,4-oxadiazole (GR175737) is a potent, selective, orally active and centally penetrating H 3 antagonist.

Neuroprotective actions of GR89696, a highly potent and selective κ‐opioid receptor agonist

1 The effect of a novel, highly potent and selective κ‐opioid receptor agonist, GR89696, has been evaluated in two animal models of cerebral ischaemia: transient bilateral carotid artery occlusion in the Mongolian gerbil and permanent, unilateral middle cerebral artery occlusion in the mouse. 2 In the Mongolian gerbil model, administration of GR89696 (3 to 30 μg kg−1, s.c.), immediately before and at 4h after insult, produced a dose‐dependent reduction in the hippocampal CA1 neuronal cell loss resulting from a 7‐min bilateral carotid occlusion. Similar effects were obtained with two other κ‐agonists, GR86014 (1 mg kg−1, s.c.) and GR91272 (1 mg kg−1, s.c.). The neuroprotective effect of GR89696 was completely blocked by prior administration of the opioid receptor antagonist, naltrexone, at 10 mg kg−1, s.c. Repeated post‐treatment with GR89696 (100 μg kg−1, s.c.) or GR44821 (10 mg kg−1, s.c.) was also effective in protecting completely the hippocampal CA1 neurones from ischaemia‐induced neurodegeneration. 3 In the permanent, unilateral middle cerebral artery occlusion model in the mouse, repeated administration of GR89696 at 300 μg kg−1, s.c. produced a 50% reduction in cerebrocortical infarct volume. In these experiments GR89696 was dosed 5 min, 4, 8, 12, 16, 20 and 24 h after occlusion on the first day and then three times daily for the next three days. GR89696 (300 μg kg−1) also produced a significant 35% reduction in infarct volume in this model when the initiation of dosing was delayed for 6 h after the insult. 4 The results indicate that the potent κ‐opioid receptor agonist, GR89696, is neuroprotective in both global and focal cerebral ischaemia models and suggest that, with this class of compound, there may be a considerable time window for pharmacological intervention.

Norbinaltorphimine: Antagonist profile at κ opioid receptors

The pharmacological profile of the opioid antagonist norbinaltorphimine has been characterised in vitro and in vivo. In vitro, norbinaltorphimine reversibly antagonised the effects of kappa agonists with pA2 values of 10.2-10.4. Norbinaltorphimine was much less potent as an antagonist at mu and delta receptors, pA2 values were 7.4-7.6 and 7.6-7.8, respectively. In all cases Schild slopes were unity. In vivo, norbinaltorphimine was an effective antagonist only at high dose levels and was not very selective between mu and kappa. The results indicate that in vitro norbinaltorphimine is a potent selective kappa antagonist; however, this antagonist profile is not maintained in vivo.

A novel series of arylpiperazines with high affinity and selectivity for the dopamine D3 receptor

Abstract A novel series of arylpiperazines has been synthesised which show high affinity for dopamine D 3 receptors. Several of these compounds exhibit ca . 100 fold selectivity for the dopamine D 3 receptor over D 1 , D 2 and D 4 receptors. In vivo studies suggest that 4 (GR103691) may have an atypical antipsychotic profile.

The selectivity of the opioid antagonist, naltrindole, for δ‐opioid receptors

Abstract— In the mouse vas deferens, naltrindole gave pKB values of 9.7, 8.3, and 7.5 at the δ‐, μ‐, and K‐sites and in binding assays, pIC50 values of 9.6, 7.8 and 7.2 at the same sites. The affinity of naltrindole for the δ binding site was increased in the presence of sodium ions and 5′‐guanylylimidophosphate. Naltrindole is, thus, a potent opioid antagonist with marked selectivity for the δ‐opioid receptor.

Reversal by β-funaltrexamine of the antinociceptive effect of opioid agonists in the rat

1 The effect of the irreversible opioid receptor antagonist, β‐funaltrexamine (β‐FNA), on antin‐ociception produced by μ‐ and κ‐receptor agonists was studied in the rat. 2 β‐FNA, 20 to 80 mg kg−1, s.c., given 24 h before testing, produced a dose‐related antagonism of the effects of morphine in the paw pressure, hotplate and tail‐flick tests. Following the 80 mg kg−1 dose, the degree of antagonism of morphine was stable for up to 48 h after dosing, but was reduced by 5 days and had disappeared by 8 days. 3 In the paw pressure test, β‐FNA, 40 mg kg−1, s.c., antagonized the effects of fentanyl, buprenorphine, tifluadom, ethylketocyclazocine and proxorphan; it was without effect against the highly selective κ‐agonist, U‐50,488. 4 In light of these results, the possible opioid receptor selectivities of both the agonists and β‐FNA are reassessed.

Profile of activity of κ receptor agonists in the rabbit vas deferens

Abstract The purpose of this study was to investigate further the κ opioid receptor selectivity of the field-stimulated isolated rabbit vas deferens preparation and to study the profile of a series of κ agonists in this tissue. Agonists acting at μ, δ and σ receptors were without detectable effect in the rabbit vas deferens. But a number of κ agonists, including bremazocine, tifluadom, ethylketocyclazocine, ketocyclazocine, U-50,488 and Win 42,610 all depressed contractions, producing parallel dose-response curves. Mr 2034 generally produced a shallower dose-response curve and achieved a lower maximum effect, thus acting like a partial agonist. The effect of ethylketocyclazocine was not reduced by the irreversible μ antagonist, β-funaltrexamine, confirming that it is not acting via μ receptors. Another group of drugs, including nalorphine, butorphanol and proxorphan, which produce an agonist action via κ receptors in the guinea-pig ileum and mouse vas deferens, were antagonists in the rabbit vas deferens, suggesting that this tissue will only respond to high efficacy κ agonists.

Novel 6-substituted 2-aminotetralins with potent and selective affinity for the dopamine D3 receptor

Starting from (1S,2R)-5-methoxy-1-methyl-2-N,N-dipropylaminotetralin [(+)-UH-232] as a lead structure, a series of novel 6-substituted 2-aminotetralins have been discovered which show high affinity for dopamine D3 receptors. One compound, GR218231, exhibits ca. 400 fold selectivity for the dopamine D3 receptor over the D2 receptor and ca. 10,000 fold selectivity with respect to D1 and D4 receptors.

Effect of β-funaltrexamine on opioid side-effects produced by morphine and U-50, 488H

Pretreatment of rats with the irreversible μ‐opioid receptor antagonist, β‐funaltrexamine (β‐FNA), 20–40 mg kg−1 s.c., produced a dose‐related antagonism of the reduction in respiratory rate, gastrointestinal (GI) propulsion, rotarod reaction latencies and body temperature produced by morphine administration 24 h later, suggesting that these effects are mediated via μ‐opioid receptors. The k‐receptor agonist, U‐50,488H, was without effect on respiratory rate at the doses tested, but produced hypothermia, sedation and low maximum inhibition of GI propulsion. These effects of U‐50, 488H were not blocked by β‐FNA suggesting that they are mediated via k‐receptors.