David I. C. Scopes

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.

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.

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.

Synthesis of imidazo-fused bridgehead-nitrogen 2′-deoxyribo-C-nucleosides: coupling-elimination reactions of 2,5-anhydro-3,4,6-tri-O-benzoyl-D-allonic acid

A short synthesis of imidazo-fused bridgehead-nitrogen 2′-deoxyribo-C-nucleosides has been developed. This is based on a coupling–elimination reaction of 2,5-anhydro-3,4,6-tri-O-benzoyl-D-allonic acid with a series of aminoalkyl-substituted heterocycles and alcohols. The intermediate α,β-unsaturated carboxamides and esters thus formed are converted into novel imidazo[1,5-a]pyridine, imidazo[1,5-b]pyridazine, and imidazo[5,1-f][1,2,4]triazine 2′-deoxyribo-C-nucleosides, including analogues of 2′-deoxyguanosine and 2′-deoxyadenosine. Assignment of the anomeric configuration of the nucleosides is made on the basis of proton n.O.e. experiments.

Characterisation of the specific binding of the histamine H3 receptor antagonist radioligand [3H]GR168320.

We have examined the specific binding of the tritiated derivative of the potent histamine H3 receptor antagonist, [3,4-3H2]-cyclohex-yl-¿[4-(3H-imidazol-4-yl)-piperidin-l-yl] iminomethyl¿- amine ([3H]GR168320), to homogenates of rat cerebral cortex. Specific binding of [3H]GR168320 at 37 degrees C associated and dissociated rapidly. Binding was saturable (Bmax 412 +/- 89 fmol/mg protein) and of high affinity (Kd 0.12 +/- 0.11 nM). Saturation studies suggested the involvement of a single site. Histamine H3 receptor agonists and antagonists inhibited [3H]GR168320 binding with high affinity. Agonist and antagonist affinities correlated when compared with affinities obtained using the tritiated histamine H3 agonist radioligand N alpha-methylhistamine.

Selective non-peptide kappa opioid receptor agonists

This article provides an overview of the development of selective K-opioid receptor antagonists as potential analgesics and neuroprotective agents. An important milestone in defining the properties of a K-receptor agonist was the discovery of the N-(2-aminocyclo-hexyl)arylacetamide class of selective K-receptor agonist, of which U-50488 was the prototype structure. Most of the subsequently reported classes of K-receptor agonist have their origins in the ethylenediamine amide pharmacophore present in U-50488. These include direct modification of U-50488 itself, structural simplification, (acyclic systems) and modification of the cyclohexane framework (piperidines and piperazines). Such strategies have provided highly potent and selective K-receptor agonists: U-62066 (spiradoline), CI-977 (enadoline), ICI199441, ZT52656 and GR89696. The full clinical picture for K-receptor agonists as analgesics or neuroprotective agents has yet to become available but initial data highlight concerns regarding side-effects ...

Benzofuran based angiotensi II antagonists related to GR117289: Part II; amino acid amides☆

Abstract A series of GR117289 derived amino acid-amide angiotensin II antagonists is described. The possibility that the amino acid-amide element of these molecules mimics the C-terminus of Angiotensin II is discounted. One of these compounds, (2g), exhibits good oral activity in the renal hypertensive rat, but has a poor pharmacokinetic profile in the dog.

A new synthesis of (±)-carbocyclic 2′-deoxyuridines

Abstract (±)-Carbocyclic 2′-deoxyuridine (1a) and its (E-5-(2-bromovinyl) derivative (1b) have been synthesized in 8 steps from (1α,3α,5α)-6-oxabicyclo[3.1.0]hexan-3-ol (2).

Synthesis of imidazo-fused bridgehead-nitrogen C-nucleosides via dehydrative coupling reactions of 2,5-anhydro-3,4,6-tri-O-benzoyl-D-allonic acid

A short, efficient synthesis of novel imidazo-fused bridgehead-nitrogen C-nucleosides has been developed. Dehydrative coupling of 2,5-anhydro-3,4,6-tri-O-benzoyl-D-allonic acid (14) with a series of aminoalkyl-substituted heterocycles (6)–(8) gives the amides (15)–(17). The latter are subsequently converted into novel imidazo[1,5-a]pyridine, imidazo[1,5-a]pyrazine, imidazo[1,5-b]pyridazine, and imidazo[5,1-f]-1,2,4-triazine C-nucleosides (20) and (21). The synthesis of a novel adenosine isostere, 8-amino-3-β-D-ribofuranosylimidazo[1,5-a]pyrazine (32), is described.