Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-10-07
1999-03-09
Henley, III, Raymond
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
A61K 3144
Patent
active
058801340
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/US96/03807 filed Mar. 20, 1996, published as WO96/32944 Oct. 24, 1996.
BACKGROUND
Serotonin mediated regulatory effects are pervasive throughout mammalian peripheral and central physiological functioning. These effects are mediated through binding of serotonin to multiple serotonin receptors at various locations in the mammalian body. Serotonin receptors in the mammalian body comprise different serotonin receptor subtypes. Serotonin binding to different receptor subtypes can cause different and often times inimical effects. Hence, in addition to the amount of serotonin released and the physiological/pathological status of a receptor, the clinical result of serotonin mediation is also affected by serotonin binding to more than one receptor subtype.
Presently, there are known to be at least 14 mammalian serotonin receptor subtypes. Recently researchers identified a novel serotonin receptor subtype designated as the "5-HT.sub.7 " receptor. mRNA for this receptor has been shown to exist in the mammalian central nervous system (CNS), kidney, vasculature, and various regions of the gastrointestinal tract. A homologous 5-HT.sub.7 receptor has also been identified in the canine coronary artery. The presence of this unique receptor in the CNS and various peripheral smooth muscle tissues, provides the possibility for new therapeutic and diagnostic modalities through agonism and antagonism of the 5-HT.sub.7 receptor.
Some compounds which bind to the 5-HT.sub.7 receptor are well known in the art. In fact, binding studies of various known agonist and antagonist compounds were used to characterize the 5-HT.sub.7 receptor. See Yong Shen et al., "Molecular Cloning and Expression of a 5-Hydroxytryptamine.sub.7 Serotonin Receptor Subtype" The J. of Biol. Chem., 264(24):18200-18204 Novel Adenylyl Cyclase-Activating Serotonin Receptor (5-HT.sub.7) Implicated in the Regulation of Mammalian Circadian Rhythms", Neuron, "Cloning of a Novel Human Serotonin Receptor (5-HT.sub.7) Positively Linked to Adenylate Cyclase", The J. of Biol. Chem., 268(31):23422-426 mammalian 5-HT.sub.7 receptor was determined by comparison of the binding affinity of various known serotonin agonist and antagonist compounds to the 5-HT.sub.7 receptor in the human, rat, and canine.
In addition to compounds which are known to bind to the 5-HT.sub.7 receptor, the use of ergoline compounds to block non-5-HT.sub.7 receptors is known in the art. However, ergoline compounds which provide selective high affinity binding to the 5-HT.sub.7 receptor to cause the central and peripheral physiological effects disclosed herein have not been described previously.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1. (Upper panel) Concentration-relaxation response to 5-HT in the absence and presence of compound II (0.3-10 .mu.M). (Lower panel) Schild plot for the data from the upper panel. The slope of the Schild regression was 0.92 and the pA.sub.2 was 6.5.
FIG. 2. Concentration-relaxation response to 5-HT in the absence and presence of compound V (1 .mu.M).
FIG. 3. Concentration-relaxation response to 5-HT in the absence and presence of compound III (1 .mu.M).
FIG. 4. (Upper panel) Concentration-relaxation response to 5-HT in the absence and presence of compound IV (10-100 nM). (Lower panel) Schild plot for the data from the upper panel.
FIG. 5. (Upper panel) Concentration-response curve for 5-HT-induced contraction in endothelium denuded canine coronary artery under basal tone in the absence and presence of compound IV (1 .mu.M). (Lower panel) Concentration-response curve for 5-MeOT-induced contraction in endothelium denuded canine coronary artery under basal tone in the absence and presence of compound IV (1 .mu.M)
FIG. 6. (Upper panel) Concentration-response curve for 5-CT-induced contraction in endothelium denuded canine coronary artery under basal tone in the absence and presence of compound IV (1 .mu.M). (Lower panel) Concentration-response curves for 5-CT-, 5-HT- and 5-MeOT-induced contraction endothelium denuded canine coronary artery un
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Cohen Marlene L
Cushing Daniel J
Boone David E.
Eli Lilly and Company
Henley III Raymond
Titus Robert D.
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