Leander Jd

Buprenorphine has potent kappa opioid receptor antagonist activity

Buprenorphine was studied for its effects on urinary output to determine if it was an agonist, partial agonist, or antagonist at the kappa receptor. Buprenorphine was a potent antagonist of bremazocine-induced urination and had no kappa agonist activity. Thus, the high affinity that buprenorphine has for the kappa receptor results in potent kappa receptor antagonist activity in vivo.Buprenorphine was studied for its effects on urinary output to determine if it was an agonist, partial agonist, or antagonist at the kappa receptor. Buprenorphine was a potent antagonist of bremazocine-induced urination and had no kappa agonist activity. Thus, the high affinity that buprenorphine has for the kappa receptor results in potent kappa receptor antagonist activity in vivo.

In vitro and in vivo antagonism of AMPA receptor activation by (3s,4ar,6r,8ar)-6-[2-(1(2)h-tetrazole-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid

The in vitro and in vivo pharmacology of a structurally novel competitive antagonist for the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) subtype of excitatory amino acid receptors is described. LY215490, (+/-)(6-(2-(1-H-tetrazol-5-yl)ethyl) decahydroisoquinoline-3-carboxylic acid), was shown to displace selectively 3H-AMPA and 3H-6-cyano-7-nitro- quinoxaline-2,3-dione (3H-CNQX) binding to rat brain membranes. LY215490 potently antagonized quisqualate-and AMPA-induced depolarizations of rat cortical slices in a competitive manner, while requiring higher concentrations to antagonize the effects of N-methyl-D-aspartate (NMDA) and kainate. In slices of rat hippocampus, LY215490 also selectively antagonized AMPA-evoked release of 3H-norepinephrine. These AMPA receptor activities were due to the (-) isomer of the compound. (3S,4aR,6R, 8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl] decahydroisoquinoline-3-carboxylic acid (LY293558). LY215490 was centrally active following parenteral administration in mice as demonstrated by protection versus maximal electroshock seizures and decreases in spontaneous motor activity. LY215490 (its active isomer being LY293558) represents a novel pharmacological agent for in vitro and in vivo studies of AMPA receptor function in the CNS.

Neuroprotectant effects of LY 274614, a structurally novel systemically active competitive NMDA receptor antagonist

Antagonists for the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor may have therapeutic potential as neuroprotectant agents in conditions of neuronal degeneration that include brain ischemia, Huntingtons chorea, and Alzheimers disease. Here we have investigated the pharmacological actions of LY 274614, a structurally novel competitive NMDA receptor antagonist, for pharmacological selectivity and neuroprotectant effects following systemic administration. LY 274614 potently displaced NMDA receptor ([3H]CGS19755) binding (IC50=58.8±10.3 nM), but had no appreciable affinity at [3H]AMPA or [3H]kainate receptor sites at up to 10,000 nM. NMDA-induced convulsions in neonatal rats or NMDA-induced lethality in mice are potently and selectively antagonized by i.p. or p.o. LY 274614. Oral doses showed a delayed but prolonged duration of effect. In adult rats, the neuro-degenerative effects (loss of choline acetyltransferase activity) following the intrastriatal infusions of NMDA or quinolinate, but not kainate, were prevented by LY 274614 (2.5 to 20mg/kg i.p.). LY 274614 is an effective neuroprotectant agent against NMDA receptor-induced toxicity when administered systemically and is a promising therapeutic agent for conditions where glutamate plays a role in the pathology of neuronal degeneration.

Anticonvulsant effects of a novel aminobenzamide (LY201116) in mice

The drug 4-amino-N-(2,6-dimethylphenyl)benzamide(LY201116) is a potent and selective anticonvulsant in the maximal electric shock test in mice. The ED50 values after oral and intravenous administration were 1.7 mg/kg and 0.51 mg/kg, respectively. For comparison, the oral and intravenous ED50 values for the anticonvulsant phenytoin which is selective for the maximal electric shock test were 9.1 and 8.5 mg/kg, respectively. After oral administration, LY201116 had a protective index (ED50 to produce neurological impairment, divided by ED50 on the maximal electric shock) of 13.5. After 4 days of administration, there was no evidence of the development of tolerance to the anticonvulsant effects of LY201116. The hexobarbital-induced sleeping time was not significantly affected by either acute or chronic administration of LY201116 for 4 days. In combination studies with the anticonvulsants phenytoin and carbamazepine which are selective for the maximal electric shock test, LY201116 produced dose-additive effects which suggest that it produces its anticonvulsant action through the same mechanism of action as these prototype anticonvulsants.