Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-04-15
2004-11-30
Aulakh, Charanjit S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S070000, C548S374100, C514S403000, C514S406000, C514S909000
Reexamination Certificate
active
06825209
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of Invention
The present invention relates to compounds that are analogs of SR141716A having unique CB1 receptor interactions and pharmacological profiles and their use in treatment of a variety of disorders such as substance abuse, obesity, schizophrenia, and memory dysfunction.
2. Discussion of the Background
The use of
Cannabis sativa, Cannabis indica
, and cannabinoid preparations in medicinal, religious, industrial, and social settings has an extensive history, with the first recorded medicinal use occurring in 2737 B.C. Despite its recognition and use as a medicinal natural product by many cultures, including that of the aboriginal in the United States, its use in western medicine began to decrease early in this century. With the passing of the Marijuana Tax Act of 1937, its cultivation and use were effectively prohibited in the U.S. In 1942, the U.S. Pharmacopeia removed marijuana from its listing. Despite marijuana usage falling into disfavor during this time, the medicinal properties of cannabis continued to be investigated. These studies were directed toward both therapeutic applications and the understanding of the mechanism(s) of action. As a result, the primary psychoactive constituent &Dgr;
9
-tetrahydrocannabinol (THC) was identified, and the structure-activity relationships (SARs) of the cannabinoids were explored (Mechoulam et al., 1970). These studies ultimately resulted in the classification of the cellular effects of a wide variety of cannabinoids in cellular and laboratory animal test systems (Martin, 1986). SARs were generated in man and laboratory animals, particularly with regard to psychotomimetic and analgesic activity (Razdan et al., 1986). Although some studies have shown therapeutic utility in the treatment of cancer chemotherapy nausea, glaucoma, and other disorders, the only therapeutic application for cannabis or cannabinoids with FDA approval is the use of Marinol® (&Dgr;
9
-THC in sesame oil) as an anti-emetic.
The continued synthesis and identification of novel cannabinoids, particularly within the last 20 years, has provided researchers with a variety of chemical probes that have facilitated a rapid expansion in the knowledge of the neurochemical substrates and mechanisms of action of cannabis and cannabinoids. The discovery of the nonclassical cannabinoids (Johnson and Melvin, 1986) and the use of the bicyclic cannabinoid [
3
H]CP55,940 as a high affinity ligand enabled the identification, localization and molecular characterization of cannabinoid receptors (Devane et al., 1988; Herkenham et al., 1990; Matsuda et al., 1990) and did much to initiate and sustain this renewed interest in cannabinoid research. Indeed, the discovery of other classes of cannabimimetic compounds such as the aminoalkylindole (WIN55212-2) and, more recently, the endogenous cannabinoid anandamide (arachidonylethanolamide; Devane et al., 1992a), were in some ways dependent upon the discovery of [
3
H]CP55,940. These compounds and others have resulted in the discovery of additional cannabinoid receptors, with the predominant form in the central nervous system (CNS) designated the CB1 site and the form found primarily in the periphery denoted the CB2 site (Munro et al., 1993). Similarly, the identification of the CB2 receptor has fostered the synthesis and characterization of receptor-selective cannabinoid ligands, such as 1-deoxy-11-hydroxy-&Dgr;
8
-THC-DMH (Huffmann et al., 1996). All of the varied structural classes of cannabinoid ligands have been examined for their selectivity at CB1 and CB2 receptor systems (Showalter et al., 1996; Felder et al., 1995) and their influence on the second messenger systems coupled to these receptor subtypes (Howlett et al., 1988; Bayewitch et al., 1995) and the endogenous neurochemicals and enzymes (Deutsch and Chin, 1993; Childers and Deadwyler, 1996) involved in cannabinoid activity. In addition to providing high affinity ligands and novel tools for examining cannabinoid mechanisms, these compounds have also provided new templates for drug discovery.
More recently, Rinaldi-Carmona et al. (1994) reported SR141716A (having the structure of Formula (I)), a potent cannabinoid antagonist with nanomolar affinity that represents a unique chemical tool for further characterizing the cannabinoid receptor system in the CNS.
That is, prior to the discovery of SR141716A, the identification of an antagonist for the cannabinoid receptor remained one of the final undiscovered pharmacological tools for further elucidating the mechanism of action and pharmacological relevance of cannabis and cannabinoids. While some compounds, such as cannabidiol or &Dgr;
9,11
-THC (Beardsley et al., 1987), had previously been reported to have antagonist activity, their potencies were extremely low. More recently, other compounds were purported to be cannabinoid antagonists, such as WIN56098, WIN54461 (Eissenstat et al., 1995) and AM630 (Pertwee et al., 1995a); however, these molecules are also less potent than SR141716A and, in the case of WIN56098, have not been convincingly shown to be antagonists (Pacheco et al., 1994). SR141716A was the first compound reported to be both an antagonist in vitro and sufficiently potent in vivo to produce a withdrawal syndrome in cannabinoid tolerant animals (Aceto et al., 1995; Tsou et al., 1995). SR141716A has also been demonstrated to have therapeutic potential in treating obesity, both in laboratory animal studies (DiMarzo et al., 2001), and in human obese males (Le Fur et al., 2001). Furthermore, SR141716A blocked acute psychological and physiological effects of smoked marijuana without altering THC pharmacokinetics (Heustis et al., 2001). Therefore, cannabinoid antagonists constitute an additional family of cannabinoid receptor ligands that are currently being considered as rational compounds for pharmacotherapeutics and structure-activity relationship analyses. It is of interest to us and other cannabinoid researchers to determine whether these compounds interact within the same recognition site on the cannabinoid receptor and whether the population of neuronal receptor sites to which SR141716A binds is the same as that with which classical and nonclassical cannabinoids interact.
Receptor-Binding Properties of SR141716A
It is generally accepted that there are two types of cannabinoid receptors: CB1 and CB2. CB1 receptors are primarily expressed in the CNS and to a lesser extent in selected tissues of the periphery; CB2 receptors have been suggested to be limited to peripheral tissues. [3H]SR141716A in vitro has high affinity for CB1 (Rinaldi-Carmoni et al., 1994; Rinaldi-Carmoni et al., 1995a; Petitet et al., 1996; Hirst et al., 1996; Thomas et al., 1997) and binds to CNS receptor populations with the same pattern of distribution (Rinaldi-Carmona et al., 1995b) as that observed with CP55,940 (Herkenham et al., 1990), 11-OH-&Dgr;
9
-THC-DMH (Thomas et al., 1992) and WIN55212-2 (Jansen et al., 1992; Kuster et al., 1993). This similarity of distribution provides further evidence that SR141716A binds specifically to neuronal cannabinoid receptors. SR141716A has marked selectivity for the CB1 over the CB2 receptor: the K
i
for CB1 is over 50-fold lower (Rinaldi-Carmona et al., 1994; Felder et al.; 1995; Showalter et al., 1996). This degree of selectivity is relatively unparalleled among cannabinoid compounds. WIN55212-2, by comparison, has approximately 20-fold (Felder et al., 1995) or 7-fold (Showalter et al., 1996) greater selectivity for CB2, while CP55,940 has approximately equal affinity at these two receptor sites.
It is important to emphasize that the nature and locus of interaction of any cannabinoid ligand with the cannabinoid receptor is unknown. Receptor mutation studies using chimeras created between CB1 and CB2 receptor sequences have shown that alterations in the extracellular loop region between helices three and four of the seven transmembrane regions differentially affect the binding of SR141716A and CP-55,940, leading Shire et al. (1996) to
Francisco Maria Elena Y.
Seltzman Herbert H.
Thomas Brian F.
Aulakh Charanjit S.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Research Triangle Institute
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