Phillip John Birch

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.

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.

Reversal by β-funaltrexamine and 16-methyl cyprenorphine of the antinociceptive effects of opioid agonists in the mouse and guinea-pig

Abstract The present study compared the effects of two opioid antagonists, β-funaltrexamine (β-FNA) and 16-methyl cyprenorphine (RX8008M) on the antinociception produced by a range of opioid agonists in the abdominal constriction test in the mouse and the paw pressure test in the guinea-pig. Both antagonists produced large shifts in the dose-response curves to the μ-agonists, morphine and fentanyl, confirming their μ-antagonist activity. Neither antagonist produced any antagonism of the antinociceptive effects of the selective κ-agonists U50488, U69593 and tifluadom, in the mouse. However, RX8008M produced small shifts in the dose-response curves to these agonists in the guinea-pig, which seems more likely to reflect μ-receptor activity of the agonists in the guinea-pig than lack of selectivity of the antagonists. Both β-FNA and RX8008M produced some antagonism of bremazocine, ethyl-ketocyclazocine, proxorphan and butorphanol, indicating that these agonists have a prominent μ-receptor component to their antinociceptive actions.

Synthesis, antinociceptive activity and opioid receptor profiles of trans-3-(octahydro-2H-pyrano[2,3-c]pyridin-4a-yl)phenols and trans-3-(octahydro-1H-pyrano[3,4-c]pyridin-4a-yl)phenols

The synthesis of a series of novel trans-3-(octahydro-2H-pyrano[2,3-c]pyridin-4a-yl)phenols (12a–g), (20a–c), (21), (22) and trans-3-(octahydro-1H-pyrano[3,4-c]pyridin-4a-yl) phenols (28a, b), (34) is described. Construction of the pyrano[2,3-c]pyridines is achieved via annulation of the pyran ring onto the arylpiperidin-3-ones (6) and (14)(R = CO2Ph). The pyrano[3,4-c]pyridines are synthesized by application of metallated enamine chemistry to 1-methyl-4-(3-methoxyphenyl)1,2,3,6-tetrahydropyridine (4) and proceeds via the novel 2-oxa-8-azabicyclo[3.3.1 ] nonane (23) and the bicyclic enamines (24) and (29). Manipulation of this general methodology has afforded a number of structural variants bearing strategic substitutions in the pyran ring as well as alternative N-groups. The antinociceptive activity and opioid receptor profile of these compounds has been determined and structure-activity relationships are discussed.

Synthesis, antinociceptive activity and opioid receptor profiles of 3-(octahydro-1H-pyrano- and -thiopyrano[4,3-c]pyridin-8a-yl)phenols

The synthesis of a series of novel cis- and trans-3-(octahydro-1H-pyrano[4,3-c]pyridin-8a-yl)phenols (13a–1), (15a, b), (20a–d), (21a–e) and the trans-3-(octahydro-1H-thiopyrano[4,3-c]pyridin-8a-yl)phenol (26) is described. Alkylation of 1-methyl-4-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridine (7) with 2-chloro-1-(chloromethoxy)ethane or 2-chloro-1-(chloromethoxy)propane, and subsequent cyclization, generated the bicyclic enamines (9a) and (9b) respectively. Hydrogenation of (9a, b) under neutral conditions provided the trans-fused octahydropyrano[4,3-c]pyridines (10a), (16a), and (17a), whereas hydrogenation of (9a) in acidic media gave the corresponding cis-fused system (11a). The trans-fused octahydrothiopyrano[4,3-c]pyridine (23) was synthesized via the analogous enamine (22). Selected N-substituents were introduced via a vinyl chloroformate N-demethylation/re-alkylation sequence and subsequent O-demethylation afforded the title phenols. The antinociceptive activity and opioid receptor profile of these compounds has been determined and structure activity relationships are discussed.