Imidazoline receptor binding compounds

Details Imidazoline receptor binding compounds Imidazoline receptor binding compounds

1998-07-22

2003-10-21

Webman, Edward J. (Department: 1617)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S411000, C514S461000, C514S636000, C514S637000

Reexamination Certificate

active

06635668

ABSTRACT:

FIELD OF THE INVENTION,
The present invention concerns compounds that have high affinity for the imidazoline receptor, particularly the imidazoline I2 receptor, methods of use thereof, and combinatorial libraries thereof.
BACKGROUND OF THE INVENTION
In the early 1980's while studying the different hypotensive effects of imidazoline compounds vs. catecholamines in the nucleus reticularis lateralis, Bousquet et al. proposed the existence of a class of imidazoline (I) binding sites distinct from adrenergic receptors (Bousquet, P. et al.,
The Journal of Pharmacology and Experimental Therapeutics
230:232-236 (1984)).
Many subsequent studies have supported the presence of these binding sites in a variety of tissues (Coupry, I. et al.,
Biochemical
&
Biophysical Research Communications
147:1055-1060 (1987); Ernsberger, P. R. et al,
European Journal of Pharmacology
134:1-13 (1987); Meeley, M. P. et al.,
Life Sciences
, 38:1119-1126 (1986); Parini, A. et al.
Journal of Biological Chemistry
264(20): 1874-8 (1989)), including the existence of the putative endogenous ligand (Atlas, D., and Y. Burstein,
European Journal of Biochemistry
144:287-293 (1984); Li, G. et al.,
Science
263:966-969 (1994)) and purification of a mitochondrial imidazoline binding site (Limon, I. et al.,
Journal of Biological Chemistry
267(30):21645-9 (1992)).
The binding sites are classified into two groups, I
1
and I
2
, according to their affinity for clonidine and idazoxan, respectively, and are located on the plasma and outer mitochondrial membranes. I
2
binding sites are associated with the monoamine oxidase protein in certain tissues and are further sub-classified into I
2A
and I
2B
depending on their sensitivity to the compound amiloride (Regunathan, S., and D. J. Reis,
Annual Review of Pharmacology
&
Toxicology
36:511-44 (1996)). A third subgroup classified as I
atypical
have been identified in the pancreatic &bgr;-cell (Morgan, N. G. et al.,
Annals of the New York Academy of Sciences
763:361-73 (1995); Brown, C. A. et al.,
British Journal of Pharmacology
108:312-317 (1993); Chan, S. L.,
Clinical Science
85(6):671-7 (1993)).
The I
1
binding sites are localized on the plasma membrane and have been found in the brainstem, kidneys, adrenal chromaffin cells, rat PC12 cells and platelets. Imidazoline I
1
receptor agonists which stimulate I
1
receptors in the medulla offer a new therapeutic approach to the treatment of hypertension and associated metabolic syndrome comprising of hyperglycemia, hyperinsulinemia, hypertriglyceridemia and low concentrations of high-density lipoprotein cholesterol (Krentz, A. J., and A. J. Evans,
The Lancet
351:152-153 (1998)). Selectivity for this receptor reduces the adverse effects attributed to stimulation of &agr;
2
-adrenoceptors such as sedation and dry mouth. Platelet I
1
receptors are upregulated in patients suffering with depression and can be downregulated with antidepressant therapy.
I
2
binding sites are more widely distributed than I
1
sites. They have been found in the nervous system (cerebral cortex, astrocytes, carotid bodies), specific organs (kidneys, liver, pancreas, colon, urethra, placenta), glands (adrenal medulla, prostate) and certain cell types (platelets, adipocytes, vascular cells). Expression of I
2
binding sites is upregulated in human brains during aging, and in patients with Alzheimer's disease. Expression is modified in the brains of depressed suicide victims (Regunathan, S., and D. J. Reis,
Annual Review of Pharmacology
&
Toxicology
36:511-44 (1996)).
Efforts have been made to identify compounds with imidazoline receptor binding affinity:
U.S. Pat. No. 5,726,197 to Clark et al. describe isoindolinyl derivatives that have imidazoline receptor binding affinity.
U.S. Pat. No. 5,686,477 to Jarry et al. describes various 5-(aryloxymethyl)oxazolines having imidazoline binding activity.
U.S. Pat. No. 5,354,769 to Garcia Sevilla et al. describes benzofuranyl imidazole derivatives having imidazoline receptor binding activity, and various uses thereof.
U.S. Pat. No. 5,732,717 to Watanabe et al. describes the use of 4-chloro-5-(imidazoline-2-ylamino)-6-methoxy-2-methylpyrimidine for treating substance abuse withdrawal.
U.S. Pat. No. 5,574,059 to Regunathan et al. describes the treatment of vascular smooth muscle cell proliferation with certain imidazoline receptor agonists.
Nevertheless, there are relatively few compounds with imidazoline receptor binding affinity available, and there is continued interest in identifying additional imidazoline receptor binding compounds.
SUMMARY OF THE INVENTION
A first aspect of the present invention is a method of binding the imidazoline receptor, comprising contacting a bis-benzene to said imidazoline receptor in an amount effective to bind to said receptor, wherein said bis-benzene contains at least one amidine group. The amidine group is covalently bound to one of the benzene rings, or an amidine group is covalently bound to both of the benzene rings (such compounds and their pharmaceutically acceptable salts are referred to as “active agents” herein). The contacting step may be carried out in vitro (e.g., with cells that express the imidazoline receptor, or with a cell-free preparation comprising the imidazoline receptor) or in vivo (e.g., by administering said compound to a subject afflicted with a disease state which is alleviable by treatment with a compound having high selectivity and affinity for the imidazoline receptor site).
A second aspect of the present invention is a method of identifying imidazoline receptor binding agents, comprising the steps of providing a library of bis-benzene compounds, said bis-benzene compound containing at least one amidine group as described above; and screening said library for compounds that bind to said imidazoline receptor. The library may be a combinatorial library, and the bis-benzene compounds may be immobilized on a solid support in accordance with known techniques (e.g., where only one of the benzene groups has an amidine group covalently bound thereto, the other benzene group may be affixed, e.g., by covalent bond, to the solid support).


REFERENCES:
patent: 5428051 (1995-06-01), Tidwell et al.
patent: 5574059 (1996-11-01), Regunathan et al.
patent: 5602172 (1997-02-01), Boykin et al.
patent: 5627184 (1997-05-01), Boykin et al.
patent: 5639755 (1997-06-01), Dykstra et al.
patent: 5643935 (1997-07-01), Dykstra et al.
patent: 5668167 (1997-09-01), Tidwell et al.
patent: 5686477 (1997-11-01), Jarry et al.
patent: 5723495 (1998-03-01), Hall et al.
patent: 5726197 (1998-03-01), Clark et al.
Wood et al., European Journal of Pharmacology, vol.. 353(1), pp. 97-103, Jul. 1998.*
D. H. Wood et al.;Pentamidine is a Potent Inhibitor of Radioligand Binding to Imidazoline Receptors, Abstracts of Interscience Conf. On Antimicrobial Agents and Chemotherapy37:280 (1997).
M. Pigini et al.;Imidazoline Receptors: Qualitative Structure-Activity Relationships and Discovery of Tracizoline and Benazoline. Two Ligands with High Affinity and Unprecedented Selectivity, Bio. &Med. Chem. 5, No. 5:833-841 (1997).
D. H. Wood et al.;1, 5-Bis(4-amidinophenoxy)pentane(pentamidine)is a Potent Inhibitor of [3H]idazoxan Binding to Imidazoine I2Binding Sites, Euro. J. of Pharmacology353:97-103 (1998).
A. Carrieri et al.;2-D and 3-D Modeling of Imidazoline Receptor Ligands: Insights into Pharmacophore, Bio. &Med. Chem. 5, No. 5:843-856 (1997).
D. H. Wood et al.;Pentamidine is a Potent Inhibitor of [3H]idazoxan Binding to Imidazoine I2Receptors, Annals New York Academy of Sciences110-113 (undated) (XP-000892876).
B. Tao et al.;Novel Bisbenzamidines and Bisbenzamidazolines as Noncompetitive NMDA Receptor Antagonists, Bio. &Med. Chem. Ltrs 9:1299-1304 (1999).
A. Yu et al.;Imidazoline Receptor Agonist Drugs: A New Approach to the Treatment of Systemic Hypertension, J. Clin. Pharmacol. 36:98-111 (1996).
S. Regunathan et al.;Imidazoline Receptors and Their Endogenous Ligands, Annu. Rev. Pharmacol. Toxicol. 36:511-544 (1996).
G. J. Molderings;Imid

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