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1 BW A868C, a novel compound, behaved as a simple competitive antagonist in a human washed platelet aggregation assay. Anti-aggregatory concentration-effect curves to BW 245C were displaced in a parallel manner. The shifts accorded with a Schild plot slope of unity and a pKB of 9.26. 2 Inhibition of platelet aggregation by prostaglandin D2 (PGD2) was antagonized with a similar potency, as were the relaxation effects of BW 245C and PGD2 in the rabbit jugular vein. BW A868C can, therefore, be classified as a DP-receptor antagonist.3 Actions of BW A868C at other prostaglandin receptors (IP, EP,, EP2, TP and FP) were excluded at concentrations up to 1,000 times higher than the DP-receptor affinity. 4 Analyses of BW 245C-and PGD2-mediated effects were complicated by additional agonist receptor interactions which were revealed by BW A868C. In rabbit jugular vein a resistant phase of agonism was detectable, indicating that both agonists exerted effects through another receptor (possibly EP2). Also, PGD2, in addition to its anti-aggregatory effect on platelets, demonstrated a pro-aggregatory action in the presence of BW A868C. 5 The contractile effects of PGD2 in guinea-pig tracheal strips were resistant to 10 tM BW A868C indicating that they were not mediated through DP-receptors. 6 To our knowledge this is the first account of a well-classified competitive antagonist at the DP-receptor. Its potency and selectivity make it an important new tool in prostanoid receptor classification and identification.

N-type calcium channels modulate the release of key pro-nociceptive neurotransmitters such as glutamate and substance P (SP) in the central nervous system. Considerable research interest has focused on the therapeutic potential of the peptidic omega-conopeptides, GVIA and MVIIA as novel analgesic agents, due to their potent inhibition of N-type calcium channels. Recently, the novel peptidic N-type calcium channel blocker, AM336, was isolated from the venom of the cone snail, Conus catus. Thus, the aims of this study were to (i) document the antinociceptive effects of AM336 (also known as CVID) relative to MVIIA following intrathecal (i.t.) bolus dosing in rats with adjuvant-induced chronic inflammatory pain of the right hindpaw and to (ii) quantify the inhibitory effects of AM336 relative to MVIIA on K+-evoked SP release from slices of rat spinal cord. Both AM336 and MVIIA inhibited the K+-evoked release of the pro-nociceptive neurotransmitter, SP, from rat spinal cord slices in a concentration-dependent manner (EC50 values=21.1 and 62.9 nM, respectively), consistent with the antinociceptive actions of omega-conopeptides. Following acute i.t. dosing, AM336 evoked dose-dependent antinociception (ED50 approximately 0.110 nmol) but the doses required to produce side-effects were an order of magnitude larger than the doses required to produce antinociception. For i.t. doses of MVIIA0.07 nmol, produced a dose-dependent decrease in antinociception but the incidence and severity of the side-effects continued to increase for all doses of MVIIA investigated, suggesting that dose-titration with MVIIA in the clinical setting, may be difficult.

1 The eects of a novel N-type voltage-operated calcium channel antagonist, o-conotoxin CVID, were compared with o-conotoxin MVIIA on sympathetic-evoked activation of right atria (RA), small mesenteric arteries (MA) and vasa deferentia (VD) isolated from the rat. Their eects were also compared on blood pressure and cardiovascular re¯exes in conscious rabbits. 2 The pIC 50 values for MVIIA and CVID, respectively, for inhibiting sympathetic-evoked responses were equivalent in RA (8.7 and 8.7) and VD (9.0 and 8.7); however, in MA the values were 8.4 and 7.7. The cardiac to vascular (RA/MA) potency ratios, antilog (plog RA ± plog MA), for MVIIA and CVID were 2 and 10. The oset rates for CVID and MVIIA were rapid, and peptide reapplication caused rapid onset of blockade, suggesting limited desensitization. 3 In the conscious rabbit, CVID and MVIIA (100 mg kg 71 i.v.) caused a similar fall in blood pressure and a tachycardia that rapidly reached maximum. Both peptides decreased the vagal-and sympathetic-mediated components of the barore¯ex, but had no eect on the vagal nasopharyngeal re¯ex. The orthostatic re¯ex to 908 tilt was blocked by MVIIA with sustained postural hypotension for 590 min after administration. In contrast, CVID caused postural hypotension at 30 min which recovered rapidly. 4 Neither CVID nor MVIIA (3 mg kg 71 i.t.) signi®cantly altered cardiovascular variables or autonomic re¯exes. 5 In conclusion, CVID appears to be relatively weak at inhibiting the re¯ex response to tilt consistent with its weaker inhibition of rat mesenteric artery constriction to perivascular nerve stimulation. This may point to subtype N-type calcium channel selectivity.

311C90 (zolmitriptan zomig: (S)-4[[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl]-2-oxazolidinone)is a novel 5-HT 1B/1D receptor agonist with proven e cacy in the acute treatment of migraine. Here, we describe the receptor speci®city of the drug and its actions on trigeminal-evoked plasma protein extravasation into the dura mater of the anaesthetized guinea-pig. 2 At the`5-HT 1B -like' receptor mediating vascular contraction (rabbit saphenous vein), the compound was a potent (p[A 50 ]=6.79+0.06) partial agonist achieving 77+4% of the maximum e ect to 5-hydroxytryptamine (5-HT). In the same experiments, sumatriptan (p[A 50 ]=6.48+0.04) was half as potent as 311C90 and produced 97+2% of the 5-HT maximum e ect. Studies in which receptor inactivation methods were used to estimate the a nity (pK A ) and e cacy relative to 5-HT (t rel. ) for each agonist con®rmed that 311C90 exhibits higher a nity than sumatriptan (pK A =6.63+0.04 and 6.16+0.03, respectively) and that both drugs are partial agonists relative to 5-HT (t rel =0.61+0.03 and 0.63+0.10, respectively, compared to 5-HT=1.0). 3 Consistent with its e ects in rabbit saphenous vein, 311C90 also produced concentration-dependent contractions of primate basilar artery and human epicardial coronary artery rings. In basilar artery, agonist potency (p[A 50 ]=6.92+0.07) was similar to that demonstrated in rabbit saphenous vein, again being 2 ± 3 fold higher than for sumatriptan (p[A 50 ]=6.46+0.03). Both agonists produced about 50% of the maximum response obtained with 5-HT in the same preparations. In rings of human coronary artery, the absolute potency of 311C90 and sumatriptan was higher than in primate basilar artery (p[A 50 ]=7.3+0.1 and 6.7+0.1, respectively), but maximum e ects relative to 5-HT were lower (37+8% and 35+7%, respectively). In both types of vessel, the inability of 5-HT 1B/1D agonists to achieve the same maximum as the endogenous agonist 5-HT is explained by the additional presence of 5-HT 2A receptors. 4 311C90 displayed high a nity at human recombinant 5-HT 1D (formerly 5-HT 1Da ) and 5-HT 1B (formerly 5-HT 1Db ) receptors in transfected CHO-K1 cell membranes (pIC 50 values=9.16+0.12 and 8.32+0.09, respectively). In intact cells, the drug produced concentration-dependent inhibition of forskolin-stimulated adenylyl cyclase (p[A 50 ]=9.9 and 9.5, respectively) achieving the same maximum e ect as 5-HT. Excepting human recombinant 5-HT 1A and 5-ht 1F receptors at which the drug behaved as an agonist with modest a nity (pIC 50 =6.45+0.11 and 7.22+0.12, respectively), 311C90 exhibited low, or no detectable a nity (pK i or pK B 4 5.5) at numerous other monoamine receptors, including other 5-HT receptor subtypes. 5 When administered to anaesthetized guinea-pigs ten minutes before unilateral electrical stimulation of the trigeminal ganglion (1.2 mA, 5 Hz, 5 ms, 5 min), 311C90 (3 ± 30 mg kg 71 , i.v.) caused a dosedependent inhibition of [ 125 I]-albumin extravasation within the ipsilateral dura mater. At the same doses, the drug also produced dose-depen...

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Highlights d NCX1 is dynamically palmitoylated at the cell surface by zDHHC5 and APT1 d Palmitoylation modifies the NCX1 dimer's structure and affinity for lipid rafts d We identify the binding site of the endogenous XIP domain in NCX1's regulatory loop d Palmitoylation modifies NCX1 XIP affinity and hence regulates intracellular Ca

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