Evolution of a novel series of [(N,N-dimethylamino)propyl]- and piperazinylbenzanilides as the first selective 5-HT1D antagonists.
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Anilides↗
Biomedical subjects
H E Connor
Publications and source records attributed to H E Connor.
Activation of sensory nerves in guinea-pig isolated basilar artery by nicotine: evidence for inhibition of trigeminal sensory neurotransmission by sumatriptan.
Nicotine (100 microM), but not electrical field stimulation or potassium chloride (0.1-3 microM), caused capsaicin (1 microM)- and tetrodotoxin (1 microM)-sensitive relaxations of guinea-pig isolated basilar artery precontracted with prostaglandin F2 alpha. Nicotine-induced responses were blocked by the neurokinin NK1 receptor antagonist, GR82334 (10 microM), but were unaffected by the calcitonin gene-related peptide (CGRP) receptor antagonist, CGRP-(8-37) (1 microM). This suggests that nicotine activates capsaicin-sensitive sensory nerves in guinea-pig basilar artery to cause relaxation predominantly via substance P release. The vascular 5-HT1 receptor agonist, sumatriptan (0.3 and 3 microM), inhibited nicotine-induced relaxation (by 50 and 80% respectively); the inhibitory effect of sumatriptan (0.3 microM) was attenuated in the presence of the non-selective 5-HT1 receptor antagonist, methiothepin (0.1 microM). These data suggest that sumatriptan can inhibit sensory neurotransmission in guinea-pig basilar artery via activation of inhibitory prejunctional 5-HT1 receptors on sensory nerve terminals.
Animals↗
The influence of the trigeminal ganglion on carotid blood flow in anaesthetized guinea-pigs.
1. The influence of the trigeminal ganglion on the carotid circulation has been investigated by measuring electrical stimulation-induced alterations in carotid arterial blood flow and resistance in anaesthetized guinea-pigs. The effects of several receptor antagonists were assessed to determine which neurotransmitters are involved in regulating carotid blood flow. 2. Arterial blood pressure and carotid vascular resistance were reduced by electrical stimulation (0.5 mA, 1 ms, 5 Hz, 60 s) of the trigeminal ganglion ipsilateral to the carotid artery from which flow was measured. No consistent effect of electrical stimulation on carotid blood flow was observed. However, when guinea-pigs were pretreated with guanethidine (30 mg kg-1, s.c., 24 h prior to experiments), stimulation produced little change in blood pressure, while carotid blood flow was increased and vascular resistance decreased, consistent with vasodilatation in the cranial circulation. Stimulation of the trigeminal ganglion contralateral to the carotid artery from which blood flow was measured, had little effect on either carotid blood flow or vascular resistance. 3. In animals pretreated with guanethidine, intravenous administration of the vasoactive intestinal polypeptide (VIP) receptor antagonist, [p-Cl-D-Phe6,Leu17]-VIP (50 micrograms kg-1) significantly attenuated the increase in carotid blood flow and decrease in carotid vascular resistance evoked by trigeminal ganglion stimulation. Responses evoked by trigeminal ganglion stimulation were, however, unaffected by intravenous injection of the tachykinin NK1 receptor antagonists, GR82334 (0.3 mg kg-1) and CP-99,994 (0.4 mg kg-1), calcitonin gene-related peptide (CGRP) receptor antagonist, CGRP8-37 (0.9 mg kg-1) and the ganglion blocking agent, hexamethonium (10 mg kg-1). 4. It is concluded that in the guanethidine-pretreated guinea-pig, electrical stimulation of the trigeminal ganglion increases carotid blood flow and produces an accompanying decrease in carotid vascular resistance, consistent with the dilatation of carotid blood vessels. The transmitter mediating this effect is most likely to be VIP.
Anesthesia↗
Neurokinin NK1 receptors mediate plasma protein extravasation in guinea-pig dura.
Selective neurokinin receptor agonists and calcitonin gene-related peptide (CGRP) were administered i.v. to anaesthetised guinea-pigs, and plasma protein extravasation was measured in dura and conjunctiva, intra- and extracranial tissues, respectively, innervated by the trigeminal nerve. The neurokinin NK1 receptor agonist, GR73632 enhanced plasma protein extravasation in guinea-pig dura (10 nmol/kg i.v.) and conjunctiva (3 and 10 nmol/kg i.v.). Pretreatment with the neurokinin NK1 receptor antagonist GR82334 (200 nmol/kg i.v.) blocked the response to GR73632 in both tissues. Neurokinin NK2 and NK3 receptor-selective agonists, GR64349 (10 nmol/kg i.v.) and senktide (30 nmol/kg i.v.) respectively, and also the neuropeptide CGRP (10 nmol/kg i.v.) had no significant effect on plasma protein extravasation in intra- or extracranial tissues. We conclude that the neurokinin NK1 receptor mediates plasma protein extravasation in tissues innervated by the trigeminal nerve in guinea-pigs; neurokinin NK2, NK3 and CGRP receptors do not directly mediate extravasation of plasma proteins in these tissues.
Animals↗
The influence of neurokinins and calcitonin gene-related peptide on cerebral blood flow in anaesthetized guinea-pigs.
The effects of systemically-administered human alpha calcitonin gene-related peptide (h.alpha CGRP), substance P and the selective neurokinin receptor agonists, GR73632 (NK1) and GR64349 (NK2) on cerebral blood flow (CBF) were studied in anaesthetized guinea-pigs using a laser-Doppler flowmeter. h.alpha CGRP (0.1 and 0.3 nmol/kg), substance P (0.03-1.0 nmol/kg), GR73632 (0.03-0.3 nmol/kg) and GR64349 (0.3 nmol/kg) each, following intra-carotid artery injection, reduced transiently (< 5 min) blood pressure and CBF. GR73632 (0.1 and 0.3 nmol/kg) and GR64349 (0.3 nmol/kg), but not h.alpha CGRP (0.01-0.3 nmol/kg) or substance P(0.01-1.0 nmol/kg), then produced a more prolonged increase in CBF, the peak effect occurring 10-15 min after injection. It is likely that this increase in CBF was due to their bronchoconstrictor activity, rather than a direct effect on the cerebrovasculature; arterial PaCO2 levels were increased and PaO2 decreased by both compounds. Following pretreatment with urea (5 M) to disrupt the blood brain barrier, h.alpha CGRP (0.1 nmol/kg) produced a significant increase in CBF (13 +/- 4%), implying that access to its receptors on the cerebrovascular smooth muscle had been achieved. Substance P (0.1 nmol/kg) remained inactive. The study has demonstrated that compounds acting on neuropeptide receptors have little direct influence on CBF following systemic administration. CGRP requires access to its receptors on the cerebrovascular smooth muscle, while selective NK1 and NK2 receptor agonists increase CBF, probably indirectly via their bronchoconstrictor activity. The lack of effect of substance P may be due to its rapid breakdown by peptidases, a property not shared by the selective neurokinin agonists.
Anesthesia↗
Extracellular recordings of membrane potential from guinea-pig isolated trigeminal ganglion: lack of effect of sumatriptan.
The aim of this study was to investigate the effect of the anti-migraine drug and selective 5-HT1 receptor agonist, sumatriptan, on membrane potential of guinea-pig isolated trigeminal ganglion. Ganglia were divided into three longitudinally, placed in two-compartment baths and the d.c. potential between compartments was recorded extracellularly. Drugs were applied to the Krebs superfusion fluid of one compartment. KCl (3 mmol/l) and GABA (0.1 mmol/l) caused depolarization (0.30 +/- 0.05 and 0.55 +/- 0.08 mV respectively, n = 11-19). 5-HT (1-10 mumol/l) caused small depolarizations (0.06 +/- 0.02 mV, n = 8) but sumatriptan (0.1-10 mumol/l) had no effect on trigeminal ganglion membrane potential. Collagenase pretreatment, to enhance desheathing, or modification of the composition of the Krebs solution failed to reveal any effect of sumatriptan. These data provide no evidence to suggest that sumatriptan inhibits neurotransmission in trigeminal ganglion. However, 5-HT1 receptors may be present in insufficient numbers in the trigeminal ganglion to elicit a change in membrane potential. Further studies are required to investigate the effect of sumatriptan at the level of the sensory nerve terminals within the intracranial vasculature, where 5-HT1 receptors may be concentrated.
Animals↗
Neurokinin-induced changes in pial artery diameter in the anaesthetized guinea-pig.
1. The effects of selective neurokinin agents on pial artery diameter, measured with an on-line image analyser, have been studied in anaesthetized guinea-pigs in order to characterize the neurokinin receptors present on pial arteries. 2. Perivascular injection of either substance P (0.01-1 microM) or the selective NK1 receptor agonists, substance P methyl ester (SPOMe, 0.01-1 microM) and GR73632 (0.1 microM), increased pial artery diameter. 3. In contrast, the selective NK2 receptor agonist, GR64349 (1 microM), produced a small vasoconstriction while the NK3 receptor-selective agonist, senktide (1 microM) was inactive. 4. Co-administration of GR82334 (1 microM), a selective NK1 receptor antagonist, inhibited the vasodilatation produced by SPOMe (0.1 microM) but not that caused by calcitonin gene-related peptide (CGRP, 0.01 microM). 5. The results are consistent with an involvement of NK1 receptors in the neurokinin-induced increase in guinea-pig pial artery diameter.
Animals↗
Lack of effect of sumatriptan and UK-14,304 on capsaicin-induced relaxation of guinea-pig isolated basilar artery.
1. The objectives of this study were to assess the effects of sensory neuropeptide antagonists and presynaptically acting receptor agonists on capsaicin-induced relaxations of guinea-pig isolated basilar artery (GPBA). 2. Capsaicin, human alpha-calcitonin gene-related peptide (CGRP) and substance P (SP) caused concentration-related relaxations of GPBA which had been pre-contracted with prostaglandin F2 alpha (PGF2 alpha). Responses to capsaicin were not modified by the peptidase inhibitors, phosphoramidon (1 microM) and bestatin (100 microM). 3. The relaxant responses to capsaicin were blocked in a selective manner by ruthenium red (3 microM) and by the CGRP antagonist, CGRP8-37 (1 microM). CGRP8-37 also selectively inhibited the relaxant effects of CGRP. 4. The selective NK1 receptor antagonist, GR82334 (10 microM), inhibited SP-induced relaxations but had little effect on capsaicin-induced relaxations. 5. The 5-HT1 receptor agonist, sumatriptan, produced small contractions of GPBA under conditions of resting tone. In the presence of PGF2 alpha, sumatriptan had no further contractile effect. Sumatriptan (0.3 and 3 microM) did not modify capsaicin-induced relaxations of GPBA. 6. The alpha 2-adrenoceptor agonist, UK-14,304 (0.1 microM), had no effect on basal or PGF2 alpha-induced tone. UK-14,304 did not modify capsaicin-induced relaxations. 7. These results suggest that capsaicin causes relaxation of GPBA via a release of CGRP. This process is amenable to blockade by CGRP8-37 and ruthenium red, but not to modulation by either sumatriptan or UK-14,304.
Animals↗
Sensory nerve-mediated relaxation of guinea-pig isolated pulmonary artery: prejunctional modulation by alpha 2-adrenoceptor agonists but not sumatriptan.
1. Effects of the alpha 2-adrenoceptor agonists, UK14304 and clonidine, the 5-HT1 receptor agonist, sumatriptan and the kappa-opioid receptor agonist, GR103545, on sensory neurotransmission in histamine-contracted guinea-pig isolated pulmonary artery (GPPA) have been studied. 2. Electrical field stimulation (EFS) induced frequency-dependent relaxations of histamine-contracted GPPA, which were attenuated by tetrodotoxin and capsaicin pretreatment but not by the nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME). 3. Substance P (0.3 microM) induced relaxations which were subject to rapid tachyphylaxis. Neither the NK1 receptor antagonist, (+/-)-CP 96,345, nor desensitization to substance P had any effect of EFS-induced relaxations of histamine-contracted GPPA. 4. Calcitonin gene-related peptide (CGRP; 3 and 30 nM) induced concentration-dependent relaxations of histamine-contracted GPPA. The putative CGRP receptor antagonist, CGRP8-37 (1 microM), markedly attenuated EFS-induced relaxations as well as relaxations induced by a low concentration of CGRP. 5. Sumatriptan (0.1 and 1 microM) and the selective kappa-opioid receptor agonist, GR103545 (10 and 100 nM) had no effect on EFS-induced relaxations of histamine-contracted GPPA. In contrast, the alpha 2-adrenoceptor agonists UK14304 (1-100 nM) and clonidine (300 nM) attenuated responses to EFS, the attenuation of UK14304 (100 nM) being reversed by yohimbine (300 nM). 6. It is concluded that in GPPA, where a presynaptic inhibition of sensory neurotransmission by alpha 2-adrenoceptor activation could be shown, there was no evidence for such modulation by either sumatriptan-sensitive 5-HT1 receptors or kappa-opioid receptors.
Adrenergic alpha-Agonists↗
Effect of sumatriptan, a selective 5-HT1-like receptor agonist, on pial vessel diameter in anaesthetised cats.
The action of sumatriptan, a selective 5-HT1-like receptor agonist that is effective for the acute treatment of migraine, was compared on pial vessel diameter following perivascular or intravenous administration to anaesthetised cats. Sumatriptan (0.01-10 microM), when microinjected perivascularly, caused a decrease in pial artery diameter (maximum change of -19 +/- 9%; mean +/- SD) but had no effect on the diameter of pial veins. Sumatriptan (1 microM)-induced pial artery vasoconstriction was unaffected by coadministration of ketanserin (1 microM) or ondansetron (1 microM) but was significantly (p less than 0.01) attenuated by methiothepin (1 microM). Intravenous infusion of a clinically effective dose of sumatriptan (64 micrograms/kg/10 min) caused selective carotid vasoconstriction (22 +/- 6% increase in carotid vascular resistance with little or no change in blood pressure or heart rate) and no change in pial artery diameter, although sumatriptan (1 microM) administered perivascularly in these animals before and after the infusion caused pial artery vasoconstriction. These results demonstrate that perivascularly administered sumatriptan causes pial artery vasoconstriction via activation of 5-HT1-like receptors. However, intravenously administered sumatriptan does not cause pial artery vasoconstriction, which suggests that sumatriptan does not readily penetrate the cerebrovascular intima.
Animals↗
Characterization of the receptor mediating relaxation to substance P in canine middle cerebral artery: no evidence for involvement of substance P in neurogenically mediated relaxation.
1. The aim of this study was to characterize the neurokinin receptor which mediates relaxation of dog isolated middle cerebral artery by the use of selective agonists and antagonists and to establish whether substance P is involved in the neurogenically mediated relaxant response in this vessel. 2. Substance P caused concentration-related, endothelium-dependent relaxations of dog isolated middle cerebral artery, contracted with prostaglandin F2 alpha. The selective NK1 receptor agonists, GR73632 and substance P methyl ester (SPOMe), also caused relaxation with similar maximum effects to those of substance P. GR73632 and SPOMe were approximately 20 times and 6 times less potent respectively than substance P. The selective NK2 and NK3 receptor agonists, GR64349 and senktide, were only weakly active in causing relaxation being at least 425 times and 245 times less potent respectively than substance P. 3. The selective NK1 receptor antagonist, GR82334, was a potent, specific, competitive antagonist of the relaxant effects of substance P. In contrast, the selective NK2 receptor antagonist, R396 (10 microM) had no effect on the response to substance P. 4. Electrical field stimulation of dog isolated middle cerebral artery, contracted with prostaglandin F2 alpha, caused neurogenically mediated, non-adrenergic non-cholinergic (NANC) relaxations. These NANC relaxations were unaffected by endothelium removal, GR82334 (10 microM) or by capsaicin (10 microM) treatment. However, the nitric oxide synthesis inhibitor, L-NG-monomethyl arginine methyl ester (L-NMMA) (100 microM) markedly attenuated the response to electrical stimulation. 5. These results suggest that substance P causes relaxation of dog isolated middle cerebral artery via activation of NK1 receptors. However, substance P does not appear to be involved in NANC neurotransmission. In contrast, the marked inhibitory effect of L-NMMA on NANC relaxations implicates nitric oxide in NANC neurotransmission in this vessel.
Animals↗
BMY 7378 is an agonist at 5-HT1A receptors mediating hypotension and renal sympatho-inhibition in anaesthetised cats.
The putative 5-HT1A receptor antagonist BMY 7378 (3-100 micrograms.kg-1 i.v.) caused reductions in blood pressure, heart rate and efferent renal nerve activity in anaesthetised cats. Similar effects were produced by the selective 5-HT1A receptor agonist, 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT 1-10 micrograms.kg-1 i.v.). The sympatho-inhibitory effects of BMY 7378 and 8-OH-DPAT, but not those of clonidine were reversed by the non-selective 5-HT1A receptor antagonist, spipirone (1 mg.kg-1 i.v.). It is concluded that BMY 7378 is an agonist at 5-HT1A receptors mediating hypotension and renal sympatho-inhibition in anaesthetised cats.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Rationale for the use of 5-HT1-like agonists in the treatment of migraine.
Migraine headache is thought to be associated with a dilatation of cranial blood vessels, particularly those in the dura mater, and an accompanying localized sterile inflammatory response. Sumatriptan is a highly selective 5-HT1-like receptor agonist which selectively constricts cranial blood vessels (including those in the dura mater). It also inhibits neurogenically-mediated plasma protein extravasation in the dura mater. Haemodynamic studies in anaesthetized animals have shown that sumatriptan selectively constricts the carotid arterial circulation and this effect appears to be restricted to an effect on carotid arteriovenous anastomoses. Sumatriptan has a much more selective pharmacological profile than ergot preparations which are also used in the acute treatment of migraine. The development of sumatriptan has been based on a vascular theory of migraine and its high degree of efficacy in the treatment of migraine strengthens the argument that dilatation of cranial blood vessels is the cause of vascular headache.
Animals↗
5-Hydroxytryptamine receptor profile.
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Coronary Disease↗
Vasodilator effect of 8-OH-DPAT in the isolated perfused mesenteric bed of the rat: no evidence for involvement of 5-HT1A receptors.
1. In the isolated perfused mesenteric bed of the rat, bolus administration or infusion of the selective 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propyl-amino) tetralin (8-OH-DPAT; bolus 0.3-90 nmoles, infusion 0.03-30 microM) caused dose-related decreases in phenylephrine-induced tone. 2. These vasodilator responses were not modified by the 5-HT1A receptor antagonists BMY7378 (0.3 microM) or cyanopindolol (0.1 microM). 3. A number of compounds, having a range of affinities for 5-HT1A receptors, were tested in the mesentery and also for antagonist activity at alpha 1-adrenoceptors in the rabbit isolated aorta. 4. The potency of 8-OH-DPAT, flesinoxan, ipsapirone, sumatriptan and phentolamine, at decreasing phenylephrine-induced tone in the mesentery correlated closely with antagonist potency at alpha 1-adrenoceptors (r = 0.99) but not with affinity at 5-HT1A binding sites (r = -0.2). 5. It is concluded that the vasodilator effect of 8-OH-DPAT in the mesenteric bed of the rat most probably reflects alpha 1-adrenoceptor antagonist activity.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Cardiovascular effects of 5-HT1A receptor agonists injected into the dorsal raphe nucleus of conscious rats.
The aim of this study was to investigate the cardiovascular effects of the 5-HT1A receptor agonists, 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), flesinoxan and 5-carboxamidotryptamine (5-CT) following injection into the dorsal raphe nucleus of conscious rats. 8-OH-DPAT (0.5-2.5 micrograms), hypotension, bradycardia and flat body posture. In contrast, injection of 8-OH-DPAT (0.5 microgram) into the median raphe nucleus caused no cardiovascular changes or flat body posture. (-)Pindolol (0.5 microgram dorsal raphe nucleus) had little effect on cardiovascular parameters, but significantly attenuated the cardiovascular effects of 8-OH-DPAT (0.5 microgram dorsal raphe nucleus). N-Methylatropine (1 mg/kg i.v.) antagonised the cardiovascular effects of 8-OH-DPAT (0.5 microgram dorsal raphe nucleus), suggesting these were vagally mediated. Both pretreatments also appeared to reduce 8-OH-DPAT-induced flat body posture. The results suggest that 8-OH-DPAT activates 5-HT1A receptors in the dorsal raphe nucleus to cause hypotension and bradycardia.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Neurogenically mediated contractions of dog basilar artery involve the release of a thromboxane-like substance.
Electrical field stimulation of dog isolated basilar artery produced neurogenically mediated contractions which were unaffected by phentolamine (1 microM), atropine (1 microM), ketanserin (1 microM) or methiothepin (0.1 microM). Responses were abolished by GR32191 (1-10 nM), BM 13.177 (0.1-10 microM) or flurbiprofen (0.5 microM) and markedly attenuated by dazoxiben (1-10 microM). Removal of the endothelium by Triton X-100-perfusion did not modify the magnitude of contractions to electrical stimulation and GR32191 still abolished the responses. GR32191 (1-10 nM) did not modify neurogenically mediated contraction of rabbit ear artery or potassium chloride-induced contraction of dog basilar artery. The results suggest that electrical field stimulation of dog basilar artery causes contractions which are mediated via a cyclo-oxygenase product with characteristics similar to thromboxane. This thromboxane-like substance is not endothelial in origin, nor released by contraction of the cerebrovascular smooth muscle per se and is therefore derived from a subendothelial, possibly neuronal, source.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
5-Hydroxytryptamine contracts human coronary arteries predominantly via 5-HT2 receptor activation.
5-Hydroxytryptamine (5-HT) caused contractions of human isolated epicardial coronary arteries which were markedly antagonised by ketanserin (10 nM-1 microM). The antagonism was not competitive. The selective 5-HT1-like receptor agonist, GR43175, caused only small, ketanserin-resistant contractions. These results suggest that the predominant contractile effect of 5-HT in human isolated large coronary arteries is mediated via 5-HT2 receptors but that, in addition, 5-HT1-like receptors contribute to some degree to this response in vitro.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗