Objective.— To study the effect of various triptan‐like drugs, eg, avitriptan, naratriptan, and sumatriptan, as well as the benzopyran alnitidan, on the natural killer cell (NKC) activity of peripheral blood mononuclear cell (PBMC) samples and highly purified NKC (HPNKC) preparations. We also examined the possible role of these agents as immunomodulators by studying their effect upon the in vitro secretion of pro‐matrix metalloproteinase‐9 (pMMP‐9) from whole blood and purified neutrophils samples.Background.— The pharmacological profile of a large number of triptan‐like compounds has been extensively studied. However, relatively little is known of their interactions with cellular components of the immune system.Methods.— Blood was obtained from nonsmoking, drug‐free healthy individuals from the Blood Bank of the University of Chile main Clinical Hospital (J.J.A.). PBMC were separated by centrifugation and HPNKC acquired by an immunomagnetic isolation procedure. NKC cytotoxicity was assayed using 51Cr‐labeled K‐562 cells as target. Addition of drugs and of effector cells (30 : 1, 50 : 1, and 70 : 1 ratio for PBMCs, and 5 : 1 for HPNKCs) was followed by incubation. Paired Student's t‐test (2‐tailed) was used to determine the significance of the specific 51Cr release in controls vs drug‐treated samples.Aliquots of whole blood or purified neutrophils were added test drug, incubated, centrifuged, and the supernatant analyzed by gelatine zymography. Gelatinolytic activity was visualized, and a digested zone at MW 92 kD indicated presence of pMMP‐9. Area of proteolysis was estimated by densitometry; prestained standards were used to assess pMMP‐9 molecular weight.Results.— Peripheral blood mononuclear cell's NKC cytotoxicity was consistently decreased after incubation with each and every one of the drugs tested. This result, observed for the 3 effector : target (E : T) cell ratios used, was relatively similar among the various compounds studied, and reached statistical significance only at E : T 70 : 1. Similar drug treatment failed, however, to produce significant changes in the cytotoxicity of HPNKC preparations, suggesting that modulation of the PBMC's NKC activity and that of HPNKC samples require different kinds of cell's derived signal. Incubation with either of the drugs tested failed to significantly alter (basal) nonstimulated pMPP‐9 secretion by whole blood samples. However, basal pMMP‐9 secretion by purified neutrophil preparations was significantly inhibited by alnitidan and sumatriptan, and not affected by naratriptan.Conclusions.— Various drugs with a triptan‐like chemical structure interact with cellular components of the innate immune system, resulting in an apparent indirect inhibition of NKC activity and direct inhibition of neutrophils pMMP‐9 secretion. These results suggest that they may play a positive role in decreasing the severity of inflammatory processes. Whether this effect is part of triptans antimigraine mechanism of action, or just an added beneficial effect of their use for the reversal treatment of migraine headaches remains to be explored.

01 Aug 2004·Journal of Pharmacology and Experimental TherapeuticsQ3 · MEDICINE

Effects of the Potential Antidepressant OPC-14523 [1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-methoxy-3,4-dihydro-2-quinolinone Monomethanesulfonate] a Combined σ and 5-HT_1A Ligand: Modulation of Neuronal Activity in the Dorsal Raphe Nucleus

Q3 · MEDICINE

Article

Author: Haddjeri, Nasser ; Bermack, Jordanna E. ; Debonnel, Guy

OPC-14523 (OPC; [1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-methoxy-3,4-dihydro-2-quinolinone monomethanesulfonate)] is a novel compound with high affinity for sigma and 5-HT(1A) receptors as well as for the 5-HT transporter. OPC has previously been shown to produce antidepressant-like effects in animal models of depression. This project set out to determine the effect of OPC on serotonergic neurotransmission and to shed light on its mechanism(s) of action. In an electrophysiological model of in vivo extracellular recordings in anesthetized rats, a 2-day treatment (1 mg/kg/day) with OPC induced a significant increase in dorsal raphe nucleus (DRN) putative 5-HT neurons' firing activity. This increase was blocked by the coadministration of NE-100 [N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)-thylamine], a selective sigma(1) antagonist (10 mg/kg/day). Furthermore, after 2-day treatments with OPC, the 5-HT(1A) autoreceptor response was altered, as demonstrated by the dramatically reduced response to an increase of endogenous 5-HT induced by the acute administration of paroxetine (500 microg/kg, i.v.). However, the 5-HT(1A) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (4 microg/kg, i.v.) maintained its ability to decrease 5-HT firing activity, an effect that was reversible by the subsequent administration of the 5-HT(1A) antagonist WAY 100635 [N-[2-(4-[2-methoxyphenyl]-1-piperazinyl)ethyl]-N-2-pyridinylcyclohexanecarboxamide] (100 microg/kg, i.v.). As 8-OH-DPAT has been shown to act preferentially through postsynaptic 5-HT(1A) receptors, our data suggests that this effect of OPC is mediated primarily by the 5-HT(1A) autoreceptor. The decreased response of the 5-HT(1A) autoreceptor to paroxetine was not blocked by the coadministration of NE-100 indicating that sigma(1) receptors are not involved in this effect. Thus, both sigma and 5-HT(1A) receptors play a role in the "antidepressant-like" effects produced by OPC, which is in keeping with previously published behavioral data. In addition, the current series of experiments suggest that OPC might have potential as an antidepressant with a rapid onset of action compared with selective serotonin reuptake inhibitor treatments, which initially suppress the firing activity of putative 5-HT neurons and require at least 2 to 3 weeks to restore the firing activity to baseline neuronal firing activity through a desensitization of the 5-HT(1A) autoreceptor.

01 Feb 2002·European Journal of PharmacologyQ3 · MEDICINE

Molecular cloning and expression of the porcine trigeminal ganglion cDNA encoding a 5-ht1F receptor

Q3 · MEDICINE

Article

Author: Hari Sharma ; Petrus Pauwels ; Pramod Ranjan Saxena ; Pankaj Bhalla ; Thierry Wurch

Using a combination of reverse transcription polymerase chain reaction (RT-PCR) and inverse-PCR techniques, we amplified, cloned and sequenced a full-length porcine 5-hydroxytryptamine 1F (5-ht(1F)) receptor complementary DNA (cDNA) derived from porcine trigeminal ganglion. Sequence analysis revealed 1101 base pairs (bp) encoding an open reading frame of 366 amino acids showing a high similarity (>90%) with the 5-ht(1F) receptor sequences from other species, including human. The recombinant porcine 5-ht(1F) receptor was expressed in African green monkey kidney cell lines (COS-7 cells) and its ligand binding profile was determined using [3H]5-HT. The affinities of several agonists (LY334370 (5-(4-fluorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole fumarate)>CP122638 (N-methyl-3 [pyrrolidin 2(R)-yl methyl]-1H-indol-5-ylmethyl sulphonamide)=naratriptan =5HT>eletriptan>sumatriptan>frovatriptan =avitriptan>dihydroergotamine>zolmitriptan>5-carboxamidotryptamine>rizatriptan>alniditan=donitriptan>L694247 (2-[5-[3-(4-methylsulphonylamino)benzyl-1,2,4-oxadiazol-5-yl]-1H-indole-3-yl] ethylamine) and putative antagonists (methiothepin>GR127935 (N-[4-methoxy-3-(4-methyl-1-piperazinyl) phenyl]-2'-methyl 4'-(5-methyl-1,2,4-oxadiazol-3-yl) [1,1-biphenyl]-4-carboxamide hydrochloride)>ritanserin>SB224289 (2,3,6,7-tetrahydro-1'-methyl-5-[2'-methyl-4'(5-methyl-1,2,4-oxadiazol-3-yl) biphenyl-4-carbonyl] furo [2,3-f] indole-3-spiro-4'-piperidine hydrochloride)>BRL155572 ([1-(3-chlorophenyl)-4-[3,3-diphenyl (2-(S,R) hydroxypropanyl)piperazine] hydrochloride)>ketanserin=pindolol) correlated highly with those described for the recombinant human 5-ht(1F) receptor (Spearman correlation coefficient; r(s)=0.942). Nevertheless, as compared to the human homologue, some triptans (i.e. sumatriptan, zolmitriptan and rizatriptan) displayed a 10- to 15-fold lower affinity for the porcine 5-ht(1F) receptor. Using RT-PCR technique, the expression of porcine 5-ht(1F) receptor mRNA was observed in cerebral cortex, trigeminal ganglion and several blood vessels, but not in skeletal muscles. In conclusion, we have cloned and established the amino acid sequence and ligand binding profile of the porcine 5-ht(1F) receptor as well as the distribution of its mRNA. This information may be helpful in exploring the role of 5-ht(1F) receptor in physiological processes and diseases, such as migraine.

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