George D. Maynard

Targeting memory processes with drugs to prevent or cure PTSD

Introduction: Post-traumatic stress disorder (PTSD) is a chronic debilitating psychiatric disorder resulting from exposure to a severe traumatic stressor and an area of great unmet medical need. Advances in pharmacological treatments beyond the currently approved SSRIs are needed. Areas covered: Background on PTSD, as well as the neurobiology of stress responding and fear conditioning, is provided. Clinical and preclinical data for investigational agents with diverse pharmacological mechanisms are summarized. Expert opinion: Advances in the understanding of stress biology and mechanisms of fear conditioning plasticity provide a rationale for treatment approaches that may reduce hyperarousal and dysfunctional aversive memories in PTSD. One challenge is to determine if these components are independent or reflect a common underlying neurobiological alteration. Numerous agents reviewed have potential for reducing PTSD core symptoms or targeted symptoms in chronic PTSD. Promising early data support drug approaches that seek to disrupt dysfunctional aversive memories by interfering with consolidation soon after trauma exposure, or in chronic PTSD, by blocking reconsolidation and/or enhancing extinction. Challenges remain for achieving selectivity when attempting to alter aversive memories. Targeting the underlying traumatic memory with a combination of pharmacological therapies applied with appropriate chronicity, and in combination with psychotherapy, is expected to substantially improve PTSD treatment.

The Newly Developed CRF1-Receptor Antagonists, NGD 98-2 and NGD 9002, Suppress Acute Stress-Induced Stimulation of Colonic Motor Function and Visceral Hypersensitivity in Rats

Corticotropin releasing factor receptor 1 (CRF1) is the key receptor that mediates stress-related body responses. However to date there are no CRF1 antagonists that have shown clinical efficacy in stress-related diseases. We investigated the inhibitory effects of a new generation, topology 2 selective CRF1 antagonists, NGD 98-2 and NGD 9002 on exogenous and endogenous CRF-induced stimulation of colonic function and visceral hypersensitivity to colorectal distension (CRD) in conscious rats. CRF1 antagonists or vehicle were administered orogastrically (og) or subcutaneously (sc) before either intracerebroventricular (icv) or intraperitoneal (ip) injection of CRF (10 µg/kg), exposure to water avoidance stress (WAS, 60 min) or repeated CRD (60 mmHg twice, 10 min on/off at a 30 min interval). Fecal pellet output (FPO), diarrhea and visceromotor responses were monitored. In vehicle (og)-pretreated rats, icv CRF stimulated FPO and induced diarrhea in >50% of rats. NGD 98-2 or NGD 9002 (3, 10 and 30 mg/kg, og) reduced the CRF-induced FPO response with an inhibitory IC50 of 15.7 and 4.3 mg/kg respectively. At the highest dose, og NGD 98-2 or NGD 9002 blocked icv CRF-induced FPO by 67–87% and decreased WAS-induced-FPO by 23–53%. When administered sc, NGD 98-2 or NGD 9002 (30 mg/kg) inhibited icv and ip CRF-induced-FPO. The antagonists also prevented the development of nociceptive hyper-responsivity to repeated CRD. These data demonstrate that topology 2 CRF1 antagonists, NGD 98-2 and NGD 9002, administered orally, prevented icv CRF-induced colonic secretomotor stimulation, reduced acute WAS-induced defecation and blocked the induction of visceral sensitization to repeated CRD.

Discovery of N-(1-Ethylpropyl)-[3-methoxy-5-(2-methoxy-4-trifluoromethoxyphenyl)-6-methyl-pyrazin-2-yl]amine 59 (NGD 98−2): An Orally Active Corticotropin Releasing Factor-1 (CRF-1) Receptor Antagonist

The design, synthesis, and structure-activity relationships of a novel series of pyrazines, acting as corticotropin releasing factor-1 (CRF-1) receptor antagonists, are described. Synthetic methodologies were developed to prepare a number of substituted pyrazine cores utilizing regioselective halogenation and chemoselective derivatization. Noteworthy, an efficient 5-step synthesis was developed for the lead compound 59 (NGD 98-2), which required no chromatography. Compound 59 was characterized as an orally bioavailable, brain penetrant, and highly selective CRF-1 receptor antagonist. Occupancy of rat brain CRF-1 receptors was quantified using ex vivo receptor occupancy assays, using both brain tissue homogenates as well as brain slices receptor autoradiography. Behaviorally, oral administration of 59 significantly antagonized CRF-induced locomotor activity at doses as low as 10 mg/kg and dose-dependently reduced the restraint stress-induced ACTH increases.

Chapter 2. Neuropeptide receptor antagonists for CNS disorders

Publisher Summary This chapter discusses the role played by neuropeptide receptor antagonists in central nervous system (CNS) disorders. Significant progress has been made in identifying and advancing non-peptidic neuropeptide receptor antagonists, with a major success achieved in bringing an NK1 antagonist to registration. Recent animal genetic models point to the potential validity of several neuropeptide receptors as targets for drug discovery, though the need for safe, efficacious compounds cannot be underestimated. Drug discovery efforts have yielded an abundance of potent and selective nonpeptidic ligands. The chapter focuses on key neuropeptides that have attracted considerable attention for their potential utility in CNS disorders, including the neurokinin (NK) peptides, neuropeptide Y (NPY), corticotropin releasing factor (CRF), and melanin-concentrating hormone (MCH). Efforts to produce antagonists have matured considerably for some of these peptide receptors to the point of clinical evaluation and even registration, whereas for others, progress is still at the preclinical stage. The chapter highlights the recent accomplishments and milestones in these drug design efforts and discusses the progress made for the emerging targets that hold considerable promise for the future.

Emergence of anti-conflict effects of zolpidem in rhesus monkeys following extended post-injection intervals

RationaleZolpidem is a hypnotic drug that binds to γ-aminobutyric acid type A receptors but lacks consistently demonstrable anxiolytic efficacy.MethodsRhesus monkeys (Nu2009=u20094) were trained under a multiple schedule in which food-maintained responding was programmed (18-response fixed ratio) for a 5-min period, followed by a 5-min period in which the food-maintained responding was suppressed by response-contingent electric shock (20-response fixed ratio). Doses of zolpidem (rangeu2009=u20090.03 to 1.0xa0mg/kg, i.v.) were administered 5xa0min before the session, and responding was re-assessed at three additional 20-min intervals. A similar experiment also was carried out with the non-selective benzodiazepine, triazolam, over a dose range of 0.001 to 0.1xa0mg/kg, i.v.ResultsZolpidem did not engender a significant increase in average rates of suppressed responding at earlier time points; however, rates of non-suppressed responding were robustly decreased. At 45- and 65-min post-injection, zolpidem treatment resulted in a dose-dependent increase in rates of suppressed responding. In contrast, the non-selective benzodiazepine triazolam increased rates of suppressed responding in a dose-dependent manner at all four time points, although decreases in non-suppressed responding were less at the later time points.ConclusionsThese findings suggest that zolpidem has anxiolytic-like effects, but only >25xa0min after i.v. injection in this rhesus monkey conflict model. It was hypothesized that time-dependent effects on the response rate-suppressing properties of zolpidem become tolerant (i.e., acute tolerance). Because anxiolytic-like effects remain stable throughout the session, the absence of rate-decreasing effects may “unmask” anti-conflict effects.