NAN-190: agonist and antagonist interactions with brain 5-HT1A receptors

Rydelek-Fitzgerald, Laura; Tietler, Milt; Fletcher, Paul W.; Ismaiel, Abd M.; Glennon, Richard A.

doi:10.1016/0006-8993(90)91759-a

Cited by 79 publications

(22 citation statements)

References 24 publications

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“…1 While the specificity of NAN-190 as a 5-HT-1A antagonist is not ideal, the other compounds used in this study have good selectivity as 5-HT-1A agonists or antagonists. has been shown to have 5-HT-1A partial agonist properties in some assays (Hjorth and Sharp, 1990;Rydelek-Fitzgerald et al, 1990), and has also been shown to have alpha-1 antagonist properties in vivo (Claustre et al, 1991). However, displays good efficacy at blocking the effects of 5-HT-1A agonists at postsynaptic receptors (Moore et al, 1993).…”

Section: Discussionmentioning

confidence: 97%

Serotonin-1A antagonists attenuate the effects of nicotine withdrawal on the auditory startle response

Rasmussen

Kallman

Helton

1997

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Withdrawal from the chronic administration of nicotine has previously been shown to lead to an enhanced auditory startle response in rats. In order to explore the neuropharmacology and neurophysiology underlying this phenomenon, we examined the effects of various 5-hydroxytryptamine (5-HT)-1A antagonists and agonists on the nicotine-withdrawal-enhanced auditory startle response in male rats. Animals were treated with nicotine (6 mg/kg/day nicotine base, via subcutaneously implanted osmotic minipumps) for 12 days. After 12 days the pumps were removed and the animals allowed to undergo spontaneous withdrawal for several days. In agreement with previous results, nicotine withdrawal led to a significant elevation of the auditory startle response. Pretreatment with the 5-HT-1A agonists (+)8-OH-DPAT (0.001-0.1 mg/kg) and LY274600 (0.3-3.0 mg/kg) either had no affect or exacerbated the nicotine-withdrawal-enhanced startle response. Pretreatment with the 5-HT-1A antagonists NAN-190 (1-3 mg/kg), LY206130 (1-10 mg/kg), or WAY-100635 (0.1-1.0 mg/kg) blocked the increase in the startle response caused by nicotine withdrawal at doses that had no effect on baseline startle responses. These data indicate that 5-HT-1A receptors play a role in the neurophysiology of nicotine withdrawal. In addition, 5-HT-1A antagonists may be able to relieve some nicotine withdrawal symptoms in man and may represent a novel pharmacotherapy for smoking cessation.

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Section: Discussionmentioning

confidence: 97%

Serotonin-1A antagonists attenuate the effects of nicotine withdrawal on the auditory startle response

Rasmussen

Kallman

Helton

1997

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“…, an arylpiperazine derivative, has a high affinity for the 5-HT 1A receptors (K i 5 0.6 nM), but it also has a high potency for the a-1 receptor (Greuel and Glaser, 1992;Perrone et al, 1995;Raghupathi et al, 1991). In addition, NAN-190 displays partial agonist-like activity (Fornal et al, 1994;Rydelek-Fitzgerald et al, 1990;Wozniak et al, 1991). BMY7378 appears to exhibit these same partial agonist properties (Greuel and Glaser, 1992).…”

Section: Introductionmentioning

confidence: 96%

p-[18F]-MPPF: A potential radioligand for PET studies of 5-HT1A receptors in humans

Shiue

Mozley

et al. 1997

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The purpose of this study was to develop a radiopharmaceutical that could be used to selectively image 5-HT1A receptors with positron emission tomography (PET). No-carrier-added 4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-[18F] fluorobenzamido]ethylpiperazine (p-[18F]-MPPF, 2) was synthesized by the nucleophilic substitution of the corresponding nitro precursor 1 with K[18F]/Kryptofix 2.2.2. in dimethyl sulfoxide (DMSO) at 140 degrees C for 20 min followed by purification with high-performance liquid chromatography (HPLC) in 10% yield in a synthesis time of 90 min from end of bombardment (EOB). Specific activity was 1-4 Ci/microM. Biodistribution studies in rats showed that the initial uptake of 2 in the brain was high (0.7% dose/g tissue at 2 min). It was then rapidly eliminated. Rates of elimination were significantly slower in brain regions with high concentrations of 5-HT1A receptors (hippocampus, cortex, and hypothalamus) than in control regions. The maximum hippocampal/cerebellar ratio was 5.6:1 at 30 min postinjection. Uptake values in serotonergic, but not in control, regions were significantly reduced by prior treatment with either (+/-)-8-OH-DPAT (2 mg/kg, i.v., 5 min prior) or WAY 100635 (1 mg/kg, i.v., 5 min prior). Radioactivity in the femur did not increase with time, suggesting that in vivo defluorination may not be the major route of metabol sm. PET studies of 2 in a monkey demonstrated selective uptake and retention of 2 in the hippocampus. The hippocampal/cerebellar ratio was 3:1 at 30 min postinjection. The ratio was reduced to 1:1 by administering (+/-)-8-OH-DPAT (2 mg/kg, i.v.) 23 min postinjection of 2. Analyses of arterial plasma by HPLC revealed that 20% of radioactivity in the plasma remained as the parent compound 2 at 30 min postinjection. The results suggest that p-[18F]-MPPF may be a useful radioligand for studying cerebral 5-HT1A receptors in humans with PET techniques.

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“…acts at the 5HT1A receptor, activating autoreceptors and functionally antagonizing post-synaptic receptors (Claustre et al, 1991;Ryldelek-Fitzgerald et al, 1990). has previously been shown to potentiate phase shifts to light (Lall and Harrington, 2006;Rea et al, 1995).…”

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confidence: 99%

NAN-190 potentiates the circadian response to light and speeds re-entrainment to advanced light cycles

2008

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Health problems can arise from de-synchrony between the external environment and the endogenous circadian rhythm, yet the circadian system is not able to quickly adjust to large, abrupt changes in the external daily cycle. In this study, we investigated the ability of to potentiate the circadian rhythm response to light as measured by phase of behavioral activity rhythms. (5 mg/kg, i.p.) was able to significantly potentiate the response to light both in dark-adapted and entrained hamsters. Furthermore, was effective even when administered up to 6 hours after light onset. Response to a light pulse was both greater in magnitude and involved fewer unstable transient cycles. Finally, was able to speed re-entrainment to a 6 h advance of the light: dark cycle by an average of 6 days when compared to vehicle-treated animals. This work suggests that compounds like NAN-190 may hold great potential as a pharmaceutical treatment for jetlag, shift work, and other circadian disorders. Keywordsserotonin; circadian; light; rhythm; jet-lag; phase shift; transient; entrainment Circadian rhythms are endogenously generated rhythms that coordinate processes such as hormone release, digestive enzyme secretion, and the sleep/wake cycle. In mammals, the major pacemaker is located in the suprachiasmatic nucleus (SCN) in the brain, which uses environmental cues to synchronize, or entrain, internal rhythms to the external surroundings (Rusak and Zucker, 1979; Ralph et al., 1990). Jetlag occurs when internal circadian rhythms become desynchronized from the external time. In humans, this desynchronization results in acute negative effects such as lowered performance levels on the job, difficulty sleeping at the appropriate times, and gastrointestinal problems. If frequent or prolonged, circadian desynchrony may be associated with more chronic health problems in people such as increased risk of breast cancer, cardiovascular disease, reproductive difficulties and peptic ulcers (Knutsson, 2003;Megdal et al., 2005). Studies using laboratory animals even link jetlag with increased rate of tumor growth and increased mortality in aged mice (Davidson et al., 2006;Filipski et al., 2004). Given the detrimental effects, studies have investigated several different methods to reduce circadian desynchrony. Melatonin, exposure to bright light, and gradual shifting of the sleep/wake cycle prior to jet travel in varying combinations have all been shown *Corresponding author. Tel: 1-413-585-3925; fax: 1-413-585-3786. E-mail address: mharring@email.smith.edu (M. Harrington). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the ...

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NAN-190: agonist and antagonist interactions with brain 5-HT1A receptors

Cited by 79 publications

References 24 publications

Serotonin-1A antagonists attenuate the effects of nicotine withdrawal on the auditory startle response

Serotonin-1A antagonists attenuate the effects of nicotine withdrawal on the auditory startle response

p-[18F]-MPPF: A potential radioligand for PET studies of 5-HT1A receptors in humans

NAN-190 potentiates the circadian response to light and speeds re-entrainment to advanced light cycles

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