Showing papers by "Frank D. Yocca published in 1998"
TL;DR: These are the first data to indicate that at least two functional populations of NPY receptors exist in the SCN, distinguishable on the basis of pharmacology, each mediating a different physiological response to NPY application.
Abstract: Neuropeptide Y (NPY) has been implicated in the phase shifting of circadian rhythms in the hypothalamic suprachiasmatic nucleus (SCN). Using long-term, multiple-neuron recordings, we examined the direct effects and phase-shifting properties of NPY application in rat SCN slices in vitro (n = 453). Application of NPY and peptide YY to SCN slices at circadian time (CT) 7.5-8.5 produced concentration-dependent, reversible inhibition of cell firing and a subsequent significant phase advance. Several lines of evidence indicated that these two effects of NPY were mediated by different receptors. NPY-induced inhibition and phase shifting had different concentration-response relationships and very different phase-response relationships. NPY-induced phase advances, but not inhibition, were blocked by the GABAA antagonist bicuculline, suggesting that NPY-mediated modulation of GABA may be an underlying mechanism whereby NPY phase shifts the circadian clock. Application of the Y2 receptor agonists NPY 13-36 and (Cys2,8-aminooctanoic acid5,24,D-Cys27)-NPY advanced the peak of the circadian rhythm but did not inhibit cell firing. The Y1 and Y5 agonist [Leu31,Pro34]-NPY evoked a substantial inhibition of discharge but did not generate a phase shift. NPY-induced inhibition was not blocked by the specific Y1 antagonist BIBP-3226; the antagonist also had no effect on the timing of the peak of the circadian rhythm. Application of the Y5 agonist [D-Trp32]-NPY produced only direct neuronal inhibition. These are the first data to indicate that at least two functional populations of NPY receptors exist in the SCN, distinguishable on the basis of pharmacology, each mediating a different physiological response to NPY application.
114 citations
TL;DR: It became evident during the course of the symposium that receptor isoforms produced by alternative splicing or mRNA editing will need to be embraced by the NC-IUPHAR scheme, yet criteria by which to judge whether these isoforms are functional, or merely the result of `leaky transcription', remain to be established.
72 citations
TL;DR: The above results suggest that the longer-lasting vasoconstrictor action of BMS-181885 on porcine carotid arteriovenous anastomoses may be related to its reported slow dissociation from 5-HT1B/1D receptor, and the drug should be able to abort migraine headaches in patients.
13 citations
12 citations
01 Jan 1998
4 citations
TL;DR: A number of second-generation agents have been developed which are structurally and pharmacologically similar to simatriptan, but have improved oral pharmacokinetic profiles, all of which have been shown to be clinically effective.
Abstract: The discovery and development of the 5-HT 1b/D agonist sumatriptan for alleviating migraine pain has been an important advance in the field of modern headache treatment and research. This important therapeutic advance is not without it's shortcomings. When administred orally, its poorly absorbed with clinically relevant headache relief occuring at least two hours afer drug administration. Due to its agonist action is peripherovascular 5-HT 1D-like receptors, it is contraindicated in patients with coronary artery disease. Furthermore, headache recurs within a 24 hour period in 40% of patients treated. Given the large unmet medical need; market size and sumitriptan's shortcomings, a number of second-generation agents have been developed which are structurally and pharmacologically similar to simatriptan, but have improved oral pharmacokinetic profiles. These include zolmitriptan, naratriptan, rizatriptan; avitriptan, alnitripan,eletriptan, and BMS-181885, all of which have been shown to be clinically effective. In this review, the SAR of the second generation triptans at the 5-HT 1B and 5-HT 1D receptors as well as distinct pharmacological actions in novel animal model are discussed