Discovery of a cyclopentylamine as an orally active dual NK1 receptor antagonist-serotonin reuptake transporter inhibitor.

Cyclopentylamine 4 was identified as a potent dual NK1R antagonist-SERT inhibitor. This compound demonstrated significant oral activity in the gerbil forced swimming test, suggesting that dual NK1R antagonists-SERT inhibitors may be useful in treating depression disorders.

Design, optimization, and in vivo evaluation of a series of pyridine derivatives with dual NK1 antagonism and SERT inhibition for the treatment of depression.

A series of substituted pyridines, ether linked to a phenylpiperidine core were optimized for dual NK(1)/SERT affinity. Optimization based on NK(1)/SERT binding affinities, and minimization of off-target ion channel activity lead to the discovery of compound 44. In vivo evaluation of 44 in the gerbil forced swim test (a depression model), and ex-vivo NK(1)/SERT receptor occupancy data support the potential of a dual acting compound for the treatment of depression.

Discovery of disubstituted piperidines and homopiperidines as potent dual NK1 receptor antagonists-serotonin reuptake transporter inhibitors for the treatment of depression.

This report describes the synthesis, structure-activity relationships and activity of piperidine, homopiperidine, and azocane derivatives combining NK1 receptor (NK1R) antagonism and serotonin reuptake transporter (SERT) inhibition. Our studies culminated in the discovery of piperidine 2 and homopiperidine 8 as potent dual NK1R antagonists-SERT inhibitors. Compound 2 demonstrated significant activity in the gerbil forced swimming test, suggesting that dual NK1R antagonists-SERT inhibitors may be useful in treating depression disorders.

Comparison of zolpidem and midazolam self-administration under progressive-ratio schedules: consumer demand and labor supply analyses.

Progressive ratio (PR) schedules of intravenous drug self-administration are useful for establishing the relationships between reinforcing effectiveness and pharmacological actions of abused drugs. The authors compared the reinforcing effects of 2 short-duration benzodiazepine-type drugs differing in their receptor selectivity: zolpidem (selective for gamma aminobutyric acid Type A [GABA(A)] receptors containing alpha1 subunits) and midazolam (nonselective). Reinforcing effectiveness was evaluated using a PR schedule of intravenous drug injection in rhesus monkeys in which the response requirement increased across the experimental session and the initial response requirement (IRR) was varied. Analyses based on consumer demand and labor supply models of behavioral economics revealed that the relative reinforcing effectiveness of zolpidem was greater than that of midazolam. For consumer demand analyses, the degree of difference between zolpidem and midazolam depended on whether price was calculated on the basis of different IRRs or different doses of drug. According to labor supply analysis, the reinforcing effects of midazolam were influenced by the economic concept referred to as a price effect to a greater degree than those of zolpidem. These findings suggest that a compound with selectivity for GABA(A) receptors containing alpha1 subunits has greater reinforcing effectiveness than a nonselective compound with similar pharmacokinetics, albeit under a limited range of conditions (high response costs). Differences in price effects may play a key role in determining the relative reinforcing effectiveness of selective versus nonselective benzodiazepine agonists.

Anti-conflict effects of benzodiazepines in rhesus monkeys: relationship with therapeutic doses in humans and role of GABAA receptors.

RATIONALE AND OBJECTIVES: Conflict procedures are used to study mechanisms underlying the anxiolytic effects of benzodiazepines (BZs). We established a conflict procedure with rhesus monkeys in order to examine the role of GABAA receptors in the anxiolytic-like effects of BZs. METHODS: Four rhesus monkeys responded under a two-component multiple schedule in which responding was maintained under a fixed-ratio schedule of food delivery in the absence (non-suppressed responding) and presence (suppressed responding) of response-contingent electric shock. RESULTS: Conventional BZs (alprazolam, flunitrazepam, clonazepam, nitrazepam, lorazepam, bromazepam, diazepam, flurazepam, clorazepate, chlordiazepoxide) engendered increases in the average rates of suppressed responding at low to intermediate doses and decreased the average rates of non-suppressed responding at higher doses. Positive correlations were observed when the therapeutic potencies of BZs in humans were compared with potencies to increase the rates of suppressed responding (R2=0.83) or decrease the rates of non-suppressed responding (R2=0.60). The 5-HT1A agonist buspirone increased the rates of suppressed responding, although the effects were modest, whereas the opioid morphine lacked anti-conflict effects. The BZ antagonist flumazenil also modestly increased the rates of suppressed responding. A relatively low dose of flumazenil enhanced, while a high dose blocked, alprazolam's anti-conflict effects. Compounds selective for alpha1 subunit-containing GABAA receptors (zolpidem, zaleplon, CL218,872) engendered relatively weak increases in the rates of suppressed responding. CONCLUSIONS: A rhesus monkey conflict procedure was established with predictive validity for therapeutic doses in people and provided evidence that anxiolytic-like effects of BZs can occur with relatively low intrinsic efficacy at GABAA receptors and are reduced by alpha1GABAA receptor selectivity.

Effects of CRF1 receptor antagonists and benzodiazepines in the Morris water maze and delayed non-matching to position tests.

RATIONALE: Benzodiazepines continue to be widely used for the treatment of anxiety, but it is well known that benzodiazepines have undesirable side effects, including sedation, ataxia, cognitive deficits and the risk of addiction and abuse. CRF(1) receptor antagonists are being developed as potential novel anxiolytics, but while CRF(1) receptor antagonists seem to have a better side-effect profile than benzodiazepines with respect to sedation and ataxia, the effects of CRF(1) receptor antagonists on cognitive function have not been well characterized. It is somewhat surprising that the potential cognitive effects of CRF(1) receptor antagonists have not been more fully characterized since there is some evidence to suggest that these compounds may impair cognitive function. OBJECTIVE: The Morris water maze and the delayed non-matching to position test are sensitive tests of a range of cognitive functions, including spatial learning, attention and short-term memory, so the objective of the present experiments was to assess the effects of benzodiazepines and CRF(1) receptor antagonists in these tests. RESULTS: The benzodiazepines chlordiazepoxide and alprazolam disrupted performance in the Morris water maze and delayed non-matching to position at doses close to their therapeutic, anxiolytic doses. In contrast, the CRF(1) receptor antagonists DMP-904 and DMP-696 produced little or no impairment in the Morris water maze or delayed non-matching to position test even at doses 10-fold higher than were necessary to produce anxiolytic effects. CONCLUSIONS: The results of the present experiments suggest that, with respect to their effects on cognitive functions, CRF(1) receptor antagonists seem to have a wider therapeutic index than benzodiazepines.

Synthesis, structure-activity relationships, and in vivo properties of 3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-ones as corticotropin-releasing factor-1 receptor antagonists.

Corticotropin releasing factor (CRF) is the primary regulator of the hypothalamus-pituitary-adrenal (HPA) axis, coordinating the endocrine, behavioral, and autonomic responses to stress. It has been postulated that small molecules that can antagonize the binding of CRF1 to its receptor may serve as a treatment for anxiety-related and/or affective disorders. Members within a series of 3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-ones, exemplified by compound 2 (IC50 = 0.70 nM), were found to be very potent antagonists of CRF1. Compound 8w showed high CRF1 receptor binding affinity and was examined further in vivo. The compound was efficacious in a defensive withdrawal model of anxiety in rats and had a long half-life and reasonable oral bioavailability in dog pharmacokinetic studies.

The anxiolytic CRF(1) antagonist DMP696 fails to function as a discriminative stimulus and does not substitute for chlordiazepoxide in rats.

RATIONALE: Compounds with a mechanism of action different from benzodiazepines may retain the anxiolytic effects of benzodiazepines with fewer side effects. CRF(1) antagonists have anxiolytic-like effects but may have different discriminative stimulus (DS) effects compared with benzodiazepines. OBJECTIVE: The present study evaluated the similarity of DS effects of a CRF(1) antagonist DMP696 to the benzodiazepine chlordiazepoxide and the ability of DMP696 to produce DS effects on its own using drug discrimination procedures, as well as its anxiolytic-like effects after acute or chronic administration. METHODS: Rats were trained to discriminate chlordiazepoxide (5.0 mg/kg, IP, 30 min prior to session) from vehicle under a fixed-ratio 10 schedule of food reinforcement and drug- or vehicle-lever selection following administration of DMP696 was determined. The effects of DMP696 on latency to exit a dark chamber (defensive withdrawal model of anxiety) were used as an index of anxiolytic-like activity. RESULTS: In chlordiazepoxide-trained rats, DMP696 (1.0-100 mg/kg, PO) resulted in most of the animals selecting the vehicle lever, as did another anxiolytic, the 5-HT(1A) partial agonist buspirone (0.3-10 mg/kg, IP). DMP696 reduced exit latency in defensive withdrawal at 10 mg/kg administered either acutely or chronically for 14 days. Thus, the doses of DMP696 studied in drug discrimination were up to 10-fold higher than those active in the anxiety model. In addition, DMP696 (10-60 mg/kg, PO) could not be established as a DS under the conditions used in this study. In a subsequent study, chlordiazepoxide was established as a DS in these same animals. CONCLUSIONS: Lack of substitution of DMP696 for the chlordiazepoxide DS in rats and its inability to acquire DS properties suggest that the DS effects of DMP696 differ from those of benzodiazepines.

Discriminative stimulus effects of zolpidem in squirrel monkeys: role of GABA(A)/alpha1 receptors.

RATIONALE: The discriminative stimulus effects of zolpidem in squirrel monkeys trained at doses greater than or equal to 3.0 mg/kg differ from those of conventional benzodiazepines (BZs), but the extent to which these effects reflect the selectivity of zolpidem for GABA(A)/alpha(1) receptors is not known. OBJECTIVES: The present study investigated the ability of GABA(A)/alpha(1)-preferring agonists to substitute for training doses of zolpidem greater than or equal to 3.0 mg/kg and the ability of GABA(A)/alpha(1)-preferring antagonists to block zolpidem's discriminative stimulus effects. METHODS: Squirrel monkeys were trained to discriminate intravenous injections of zolpidem (3.0 or 5.6 mg/kg) from saline and tested with BZ agonists differing in selectivity and efficacy at GABA(A)/alpha(1) receptors. Antagonism of the effects of zolpidem was studied using the GABA(A)/alpha(1)-preferring antagonists beta-carboline-3-carboxylate-t-butyl ester (beta-CCT) and 3-propyloxy-beta-carboline (3-PBC). RESULTS: Zolpidem and quazepam (GABA(A)/alpha(1)-preferring agonist) engendered full substitution for zolpidem, whereas CL 218,872 (GABA(A)/alpha(1)-preferring partial agonist) and the non-selective BZ agonists alprazolam and flunitrazepam engendered low and variable levels of zolpidem-lever responding (35-58%). Both beta-CCT and 3-PBC antagonized the discriminative stimulus effects of zolpidem in a surmountable fashion. CONCLUSIONS: Our findings provide evidence for a key role of GABA(A)/alpha(1) receptors in the discriminative stimulus effects of zolpidem at relatively high training doses, and suggest that selectivity and relatively high efficacy at GABA(A)/alpha(1) receptors is required for BZ agonists to reproduce these discriminative stimulus effects.

The CRF(1) receptor antagonist DMP696 produces anxiolytic effects and inhibits the stress-induced hypothalamic-pituitary-adrenal axis activation without sedation or ataxia in rats.

RATIONALE: CRF(1) antagonists may be effective in the treatment of anxiety disorders while having fewer side effects compared with classical benzodiazepines. OBJECTIVES: The effects of a small molecule selective CRF(1) antagonist DMP696 on anxiety-like behaviors and stress-induced increases in corticosterone in rats exposed to a novel environment and on locomotor activity and motor coordination were determined in rats. These effects of DMP696 were compared with those produced by the classical benzodiazepine chlordiazepoxide (CDP). METHODS: DMP696 or CDP were administered PO, 60 minutes before behavioral testing in rats. Their effects on latency to exit a dark chamber and stress-induced increase in corticosterone in the Defensive Withdrawal test (an animal model of anxiety), locomotor activity, and rotorod performance (measure of ataxia) were determined. RESULTS: DMP696 significantly reduced exit latency and reversed the stress-induced increase in corticosterone in the Defensive Withdrawal test at doses of 3.0-10 mg/kg and higher. In contrast, CDP significantly decreased exit latency at 10 and 30 mg/kg, but not at 100 mg/kg, due to concurrent non-specific side effects. Unlike DMP696, CDP had no effect on the stress-induced increase in corticosterone at lower doses, but resulted in a significant increase at higher doses. DMP696 did not reduce locomotor activity or impair motor coordination at doses up to 30-fold higher than doses effective in the Defensive Withdrawal model. In contrast, CDP produced significant sedation and ataxia at the same doses that were effective in reducing exit latency. CONCLUSIONS: These data suggest that the CRF(1) antagonist DMP696 might retain the therapeutic benefits of classical benzodiazepines but have fewer motoric side effects.