Kenneth D. Wild

Cocaine place preference is blocked by the δ-opioid receptor antagonist, naltrindole

Naltrindole, a selective delta-opioid receptor antagonist, was evaluated for its potential to block the reinforcing properties of cocaine using a conditioned place pairing paradigm in Lewis rats. Cocaine HCl (15 mg/kg s.c.) produced a strong place preference which was significantly blocked in animals pretreated with naltrindole (3 mg/kg i.p.); naltrindole alone showed no reinforcing or aversive effects. The results suggest a novel approach for the treatment of cocaine abuse in man.

Opioid δ receptor subtypes are associated with different potassium channels

The purpose of the present experiment was to determine (a) whether the antinociceptive actions of [D-Pen 2 , D-Pen 5 ] enkephalin (DPDPE) could also be linked to a glyblenclamide-sensitive potassium channel (presumably an ATP-sensitive potassium channel) and (b) whether the antinociceptive actions of [D-Ala 2 ] deltorphin II were associated with potassium channels and if so, whether these channels were also of the glyblenclamide-sensitive type

2,3-Dihydro-dithiin and -dithiepine-1,1,4,4-tetroxides: small molecule non-peptide antagonists of the human galanin hGAL-1 receptor

The neuropeptide galanin modulates several physiological functions such as cognition, learning, feeding behavior, and depression, probably via the galanin 1 receptor (GAL-R1). Using an HTS assay based on 125I-human galanin binding to the human galanin-1 receptor (hGAL-R1), we discovered a series of 1,4-dithiin and dithiipine-1,1,4,4-tetroxides that exhibited binding affinity IC50s to hGAL-R1 ranging from 190 to 2700 nM. Two of the dithiepin analogues, 7 and 23, behaved pharmacologically as hGAL-R1 antagonists in secondary assays involving adenylate cyclase activity and GTP binding to G-proteins. Analogues 7 and 23 were also active in functional assays involving galanin, reversing the inhibitory effect of galanin on acetylcholine (ACh) release in rat brain hippocampal slices and electrically-stimulated guinea pig ileum twitch.

Binding of BW 373U86, a non-peptidic δ opioid receptor agonist, is not regulated by guanine nucleotides and sodium

BW 373U86 is a novel, non-peptidic delta-opioid receptor ligand with agonist properties in mouse brain and in the mouse isolated vas deferens. The sensitivity of BW 373U86, and of the peptide delta-opioid agonists [D-Pen2,D-Pen5]enkephalin (DPDPE) and [D-Ala2,Glu4]deltorphin, to regulation by guanine nucleotides and sodium was evaluated in competition studies against the 5 selective radioligand [3H]naltrindole. The IC50 values for DPDPE and [D-Ala2,Glu4]deltorphin were significantly increased in brain and mouse vas deferens in the presence of Gpp(NH)p and NaCl. In contrast, the IC50 values for BW 373U86 were not altered in the presence of Gpp(NH)p and NaCl in either tissue. The data indicate that the agonist properties of BW 373U86 may not be affected by the supposed uncoupling of the alpha-subunit of the G-protein from a receptor thought to be G-protein linked.

Chapter 2. Centrally Acting Analgesics

Publisher Summary The relief of chronic pain is the goal of medicinal chemistry research in the area of analgesia. There continues to be a high need for new agents to lessen the sensation of pain, especially the chronic pain. The present availability of human cloned opioid receptor subtypes allows for the directed synthesis of subtype-selective agents that could have morphine-like anti-nociception, but without the abuse liability, sedation, and respiratory depression that restrict the use of current opioids. Nonopioid analgesics have the inherent advantage of lacking opioid-related side-effects. As with opioids, receptor sub-type selective agents, such as for α 2 -adrenoceptor agonists, may provide the best combination of analgesia relative to limiting the side-effects. Further, the central activity of “peripherally acting” nonsteroidal anti-inflammatory drugs (NSAIDs) and the peripheral action of “centrally-acting” opioids has become better appreciated. In the clinical area, alternative routes of administration, such as oral morphine, nasal spray, transdermal patch, spinal administration, and patient controlled analgesia (PCA) have become increasingly utilized, particularly for chronic pain. Two noteworthy drugs are an injectable NSAID (Toradol’ ketoralac), which has achieved clinical favor, and Ultram’ tramadol HCI, the first centrally acting oral analgesic after a long time. The chapter discusses the general scientific and patent literature on centrally acting analgesics during 1994, with lesser coverage of important findings during 1990-1993.