In vitro and in vivo comparison of two non-peptide tachykinin NK3 receptor antagonists: Improvements in efficacy achieved through enhanced brain penetration or altered pharmacological characteristics

Dawson, Lee A.; Langmead, Christopher J.; Dada, Adeshola; Watson, Jeannette M.; Wu, Zining; Flor, Raúl de la; Jones, Gareth; Cluderay, Jane E.; Southam, Eric; Murkitt, G.S.; Hill, M. J.; Jones, Declan N.C.; Davies, Ceri H.; Hagan, Jim J.; Smith, Paul W.

doi:10.1016/j.ejphar.2009.10.054

Cited by 9 publications

(11 citation statements)

References 36 publications

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“…However, in animal studies, we were able to show penetration of blood-brain barrier by radiolabeled AZD2624 in gerbil brain, with approximately brain-to-plasma ratio of 0.2. 6 Moreover, AZD2624 stimulated release of endogenous dopamine evidenced by lowered 11 C-MNPA binding in monkey brain. 10 Finally, further evidence of brain bioavailability comes from studies of AZD2624 in healthy human volunteers, including sleep disturbance, headache, and centrally medicated depression of plasma testosterone.…”

Section: Discussionmentioning

confidence: 99%

“…7 Because frontal cortical dopaminergic hypofunction has been hypothesized to underlie negative and cognitive deficits of schizophrenia, NK 3 antagonists may potentially remedy these deficits by increasing frontal cortical dopamine release. 6,7 Support for these hypotheses comes from a 6-week, double-blind, multicenter, placebo-and haloperidol-controlled metatrial of 4 experimental compounds, among which the NK 3 antagonist osanetant showed efficacy for total and positive symptoms measured on the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Inventory, statistically significantly different from placebo and comparable to haloperidol. 8 These findings, however, could not be replicated for the NK 3 antagonist talnetant, which may have been related to its poor bioavailability in the central nervous system.…”

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confidence: 97%

“…Because mesolimbic dopaminergic overactivity is hypothesized to underlie positive symptoms in schizophrenia, it is possible that NK 3 antagonists may decrease positive symptoms by inhibiting mesolimbic dopaminergic activity. 5,6 In addition, systemic administration of NK 3 antagonists (eg, talnetant) has been shown to increase the levels of dopamine in prefrontal cortex. 7 Because frontal cortical dopaminergic hypofunction has been hypothesized to underlie negative and cognitive deficits of schizophrenia, NK 3 antagonists may potentially remedy these deficits by increasing frontal cortical dopamine release.…”

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confidence: 99%

“…8 These findings, however, could not be replicated for the NK 3 antagonist talnetant, which may have been related to its poor bioavailability in the central nervous system. 2,6 In the current study, we investigate the efficacy, tolerability, and cognitive effects of AZD2624 (Fig. 1).…”

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confidence: 99%

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The Selective Neurokinin 3 Antagonist AZD2624 Does Not Improve Symptoms or Cognition in Schizophrenia

Litman

Smith

Desai

et al. 2014

Journal of Clinical Psychopharmacology

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Problems with the efficacy of second-generation antipsychotics on negative symptoms and cognition have highlighted the need for further development of drugs targeting central nervous system neurotransmitter systems other than dopamine. One target in development is neurokinin 3 (NK(3)) tachykinin receptors, which are coreleased and interact with dopamine. This study investigates the efficacy, tolerability, and cognitive effects of AZD2624, a selective, orally active NK(3) receptor antagonist, in symptomatic patients with schizophrenia. Patients were randomly assigned to 1 of 3 treatment groups: AZD2624 40 mg, placebo, or olanzapine 15 mg. Treatment lasted for 28 days, and the Positive and Negative Syndrome Scale, the Clinical Global Impression Severity Scale and Improvement Scales, and cognition as assessed by CogState were used as primary outcome measures. There were no significant differences in patients treated with AZD2624 versus placebo on change in Positive and Negative Syndrome Scale total score and Clinical Global Impression Severity Scale; in addition, no change in CogState measures was found. Results of the trial do not support a role for the NK(3) antagonist AZD2624 as a therapeutic treatment for acute schizophrenia when used as monotherapy.

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Section: Discussionmentioning

confidence: 99%

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confidence: 97%

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confidence: 99%

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confidence: 99%

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The Selective Neurokinin 3 Antagonist AZD2624 Does Not Improve Symptoms or Cognition in Schizophrenia

Litman

Smith

Desai

et al. 2014

Journal of Clinical Psychopharmacology

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“…2 As a result, it was hypothesized that NK3 receptor antagonists may decrease positive schizophrenia symptoms by inhibiting mesolimbic dopaminergic activity. 3,4 However, a double-blind, placebo-controlled, proof-of-concept clinical trial of AZD2624 failed to show efficacy in schizophrenia. 1 Notable side effects were observed during the early development program, where luteinizing hormone (LH) and testosterone levels in healthy male subjects were decreased.…”

mentioning

confidence: 99%

Population Pharmacokinetic and Pharmacodynamic Modeling of AZD4901 and Simulation to Support Dose Selection for the Phase 2a Study

Webber

et al. 2016

The Journal of Clinical Pharma

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Significant and reversible reductions in testosterone levels were observed with AZD4901 in both preclinical and clinical testing. A comprehensive population pharmacokinetic/pharmacodynamic (PK/PD) modeling of AZD4901 concentration and testosterone relationship from 3 phase 1 studies was performed using NONMEM to support dose selection for phase 2a development. A 2-compartment model with first-order absorption and first-order elimination best described AZD4901 PK. Circadian rhythm of baseline testosterone concentrations was well described by a cosine function. An indirect response model with inhibition of testosterone production was used to link the AZD4901 concentration to testosterone response. The AZD4901 concentration to yield 50% maximum testosterone suppression (IC50) was estimated to be 230 ng/mL. Based on simulations, following 40 mg twice daily (BID) treatment, the AZD4901 steady-state trough concentration will be much higher compared to 80 mg once daily (QD). The AZD4901 concentration time above IC50 after 40 mg BID is 84% of the time of the dosing interval compared to only 49% after 80 mg QD. The mean predicted testosterone concentrations at steady state are lower and overall less variable over 24 hours for 40 mg BID dosing compared to 80 mg QD dosing. Population PK and PK/PD analyses demonstrated that AZD4901 40 mg BID is a better dosing strategy to more consistently suppress testosterone during the entire dosing interval. Consequently, 40 mg BID dosing was suggested in a phase 2a trial in females with polycystic ovary syndrome, and the trial resulted in a positive outcome as shown by significant testosterone decrease compared to placebo.

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Kisspeptin and neurokinin B analogs use in gynecological endocrinology: where do we stand?

Szeliga

Podfigurna

Bala

et al. 2019

J Endocrinol Invest

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Background Recent studies have found that kisspeptin/neurokinin B/dynorphin neurons (KNDy neurons) in the infundibular nucleus play a crucial role in the reproductive axis. Analogs, both agonists and antagonists, of kisspeptin and neurokinin B (NKB) are particularly important in explaining the physiological role of KNDy in the reproductive axis in animals. The use of kisspeptin and NKB analogs has helped elucidate the regulators of the hypothalamic reproductive axis. Purpose This review describes therapeutic uses of Kiss-1 and NKB agonists, most obviously the use of kisspeptin agonists in the treatment for infertility and the induction of ovulation. Kisspeptin antagonists may have potential clinical applications in patients suffering from diseases associated with enhanced LH pulse frequency, such as polycystic ovary syndrome or menopause. The inhibition of pubertal development using Kiss antagonists may be used as a therapeutic option in precocious puberty. Kisspeptin antagonists have been found capable of inhibiting ovulation and have been proposed as novel contraceptives. Hypothalamic amenorrhea and delayed puberty are conditions in which normalization of LH secretion may potentially be achieved by treatment with both kisspeptin and NKB agonists. NKB antagonists are used to treat vasomotor symptoms in postmenopausal women, providing rapid relief of symptoms while supplanting the need for exogenous estrogen exposure. Conclusions There is a wide spectrum of therapeutic uses of Kiss-1 and NKB agonists, including the management of infertility, treatment for PCOS, functional hypothalamic amenorrhea or postmenopausal vasomotor symptoms, as well as contraceptive issues. Nevertheless, further research is needed before kisspeptin and NKB analogs are fully incorporated in clinical practice.

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In vitro and in vivo comparison of two non-peptide tachykinin NK3 receptor antagonists: Improvements in efficacy achieved through enhanced brain penetration or altered pharmacological characteristics

Cited by 9 publications

References 36 publications

The Selective Neurokinin 3 Antagonist AZD2624 Does Not Improve Symptoms or Cognition in Schizophrenia

The Selective Neurokinin 3 Antagonist AZD2624 Does Not Improve Symptoms or Cognition in Schizophrenia

Population Pharmacokinetic and Pharmacodynamic Modeling of AZD4901 and Simulation to Support Dose Selection for the Phase 2a Study

Kisspeptin and neurokinin B analogs use in gynecological endocrinology: where do we stand?

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