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(12) United States Patent (10) Patent No.: US 6,964,958 B2 Auta Et Al

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(12) United States Patent (10) Patent No.: US 6,964,958 B2 Auta Et Al USOO6964958B2 (12) United States Patent (10) Patent No.: US 6,964,958 B2 Auta et al. (45) Date of Patent: Nov. 15, 2005 (54) METHOD OF SIMULTANEOUSLY (51) Int. Cl." ................................................ A61K 31/55 TREATING SENSORY AUDITORY GATING (52) U.S. Cl. ....................... 514/220; 514/962; 424/451; DEFICT AND ASSOCATED PSYCHOSIS IN 424/464 SCHIZOPHRENIA AND BIPOLAR (58) Field of Search ................................. 514/220,962; DSORDER PATIENTS WITH MANIA 424/451, 464 (76) Inventors: James Auta, 2314 W. Flournoy St., Chicago, IL (US) 60612; Erminio (56) References Cited Costa, 333 E. Ontario (#3302b), Chicago, IL (US) 60611; John M. U.S. PATENT DOCUMENTS Davis, 442 Webster Ave., Chicago, IL 4,180,668 A 12/1979 Hester, Jr. ................... 540/566 (US) 60614; Alessandro Guidotti, 859 5,317,018 A * 5/1994 Walser et al. ..... ... 514/220 N. Dearborn, Chicago, IL (US) 60610; 6,528,649 B2 3/2003 Cai et al. ...................... 546/84 Patricia Tueting, 488 Ash St., Winnetka, IL (US) 60693 FOREIGN PATENT DOCUMENTS (*) Notice: Subject to any disclaimer, the term of this EP O 573 982 12/1993 patent is extended or adjusted under 35 * cited by examiner U.S.C. 154(b) by 0 days. Primary Examiner Frederick Krass (21) Appl. No.: 10/252,030 (74) Attorney, Agent, or Firm-Ladas and Parry LLP (22) Filed: Sep. 20, 2002 (57) ABSTRACT (65) Prior Publication Data Schizophrenia and bipolar disorders with mania may be US 2003/0119821 A1 Jun. 26, 2003 treated by imidazenil or other benzodiazepine-3- Related U.S. Application Data carboxamide derviatives. (60) Provisional application No. 60/325,672, filed on Sep. 28, 2001. 5 Claims, 6 Drawing Sheets U.S. Patent Nov. 15, 2005 Sheet 1 of 6 US 6,964,958 B2 | U.S. Patent Nov. 15, 2005 Sheet 2 of 6 US 6,964,958 B2 ZCHRITIÐIH U.S. Patent US 6,964,958 B2 U.S. Patent Nov. 15, 2005 Sheet 5 of 6 US 6,964,958 B2 Table 1. Proposed roles of GABAA-receptor subtypes in benzodiazepine actions O. Cl2 C Ocs Sedation -- - -- Amnesia -- - Seizure protection -- -H Anxiolysis -- From Mohler 1999, 2001 (modified) FIGURE 5 U.S. Patent Nov. 15, 2005 Sheet 6 of 6 US 6,964,958 B2 US 6,964,958 B2 1 2 METHOD OF SIMULTANEOUSLY and may contribute to Sensory gating deficits and to the TREATING SENSORY AUDITORY GATING presence of Visual and auditory hallucinations, cognitive DEFICT AND ASSOCATED PSYCHOSIS IN impairment, and Social withdrawal. As a general Strategy, SCHIZOPHRENIA AND BIPOLAR our Studies are directed at testing whether drugs that tend to DSORDER PATIENTS WITH MANIA normalize a deficient GABAergic System may also be ben eficial in correcting the deficit of auditory gating in Schizo phrenia. This deficit, commonly known as a defective Priority is claimed from U.S. Provisional patent appli prepulse inhibition of startle (PPI) is considered the most cation 60/325,672 filed Sep. 28, 2001. important among the few objective measurements of brain FIELD OF THE INVENTION neuronal network functional alterations that can be mea Sured in patients with psychotic disorders and in their The present invention relates to the treatment of patients relatives (Swerdlow & Geyer, 1998). Suffering from Schizophrenia and patients Suffering from New therapeutic opportunities arise today due to increas bipolar disorders with mania. ing insights into the molecular architecture and diversity of 15 components involved in Signal transduction at GABAA BACKGROUND OF THE INVENTION receptors (FIG. 2). Based on the brain expression of seven GABAergic inhibition is increasingly considered one of Subunit families comprising at least 18 different Subunits the most important factors in controlling the mode of (c. 1-6, B1–3, 6, e, 0, p1-3) that are assembled in hetero operation of thalamo-cortical and re-entrant cortico pentameric GABAA receptors, an extraordinary Structural thalamic pathways as well as of the afferent Septal heterogeneity of the target for GABA is operative in the hippocampus and of the re-entrant hippocampal-Septal CNS (Barnard, 2001). Most GABAA receptor subtypes in glutamatergic pathways that are Substrates for the regulation brain are believed to be composed of C. By Subunits associ of complex brain functions, including normal Sensory, ated to form the above-mentioned heteropentameric Struc gating, cognition, Vigilance, Spatial Orientation, Volition, and tures termed GABAA receptors (FIG. 2). Although the consciousness. These functions are altered in Schizophrenia 25 physiological Significance of this heterogeneity is only par and bipolar disorder patients with mania. Thus, one may tially understood, the pharmacological Significance of the attribute the appearance of psychotic Symptoms in these various Subunits with respect to, their association with mental disorders to a deficit in GABAergic modulation in various actions of anxiolytic benzodiazepines and congeners critical cortico-thalamic and cortico-hippocampal brain cir is beginning to be quite well understood. For example, cuits. GABAA receptors containing C. and Y Subunits are Substrates Indeed, Schizophrenia and bipolar disorder patients with for a wide Spectrum of actions elicited by clinically available mania who manifest an auditory gating deficit and who agonists acting at the modulatory benzodiazepine binding Suffer from other associated problems, Such as auditory Sites. These sites are located at the interface of the postsyn hallucinations, cognitive impairment, delusions, and defects aptic ectodomains of contiguous C. and Y Subunits on of volition (lack of motivation, flat affect, and Social 35 GABAA receptors composed of C. By subunits (FIG. 2). withdrawal), express downregulation of GABAergic Syn Benzodiazepine-Sensitive GABAA receptors are character thesis and function in their cortical, thalamic, Septal, and ized by the expression of C., C. C. or C. Subunits in their hippocampal circuits (Guidotti et al., 2000). The neuroana heteropentameric Structure and by the contiguity of these C. tomical and neurochemical abnormalities of the GABAergic subunits with Y subunits. The GABA-gated ion channel System in postmortem brain of patients with Schizophrenia 40 opening frequency of these receptorS is promptly enhanced and bipolar disorder with mania can be Summarized as to maximal efficacy by agonists of benzodiazepine Sites follows: 1) decreased GABA release and uptake (Reynolds currently available on the US market and this is the basis for et al., 1990; Sherman et al., 1991; Simpson et al., 1998); 2) their therapeutic effectiveness in the treatment of anxiety increased denervation-dependent GABAA receptor density disorders, Sleep disturbances, muscle Spasms, and epilepsy. measured by H-muscimol binding, particularly in layer II 45 However, maximal amplification of GABA-gated channels of the prefrontal cortex (PFC) and in superficial layers of by benzodiazepines is also the basis of undesirable Side other adjacent cortical areas (Benes et al., 1992, Benes, effects, Such as Sedation, amnesia, tolerance, and depen 2000); 3) increased expression of the Cl GABAA receptor dence (Costa and Guidotti, 1996). subunit mRNA in the PFC (Impagnatiello et al., 1998); 4) a In present clinical practice the consensus is that in Schizo dorsolateral PFC decrease of presynaptic GABA transporter 50 phrenia protracted benzodiazepine monotherapy is not 1-positive cartridges in GABAergic axon terminals of chan effective, despite anecdotical reports of antipsychotic effi delier cells impinging on the initial Segments of pyramidal cacy in the first few days of treatment. The lack of antip axons (Woo et al., 1998), and decreased GAD, expression Sychotic action after protracted benzodiazepine treatment is (this enzyme is important in the Synthesis of GABA and is presumably attributable to the well known phenomenon of one of the two molecular forms of glutamic acid decarboxy 55 tolerance that inevitably and rapidly occurs after adminis lase expressed in GABAergic neurons, the other being tration of clinically-available benzodiazepine. Moreover GADs) (Akbarian et al., 1995; Impagnatiello et al., 1998; their use is generally contraindicated because dlinically Benes 2000; Bunney and Bunney, 2000; Guidotti et al., available benzodiazepine drugs also elicit Sedation and 2000; Volk et al., 2000), which taken together suggest that amnesia, and if used repeatedly in addition to tolerance GABAergic function may be downregulated; and 5) an 60 produce dependence (Costa et al., 2001). altered cortical distribution of nicotinamide adenine dinucle Recent studies (Mohler, 2001) have established that the otide phosphate-positive GABAergic cells (Akbarian et al., Sedative and amnestic action of benzodiazepines is related to 1996). the amplification of GABA action at GABA. C. receptors Collectively, these data Support the hypothesis that including C. Subunits contiguous to the Y. Subunits, whereas GABAergic downregulation in cortical and hippocampal 65 their anxiolytic and anticonvulsant and antipsychotic actions networks involved in Sensory information processing act as are mediated presumably by Similar actions at GABAA a Vulnerability factor in the etiopathogenesis of psychosis receptors having C, Cl- or Cs receptor Subunits (Table 1). US 6,964,958 B2 3 4 Thus, opportunities for the design of a new generation of FIG. 2 is a diagram of a GABAA receptor. benzodiazepine binding site ligands that are partial agonists FIG. 3 is a Table showing the effect of imidazenil on and act specifically at GABAA receptor Subtypes, are now prepulse inhibition of Startle in wild type mice and heterozy
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