Pharmacological profile of 2-bromoterguride at human dopamine D2, porcine serotonin 5-hydroxytryptamine 2A, and α2C-adrenergic receptors, and its antipsychotic-like effects in rats.

Dopaminergic, serotonergic, and adrenergic receptors are targets for therapeutic actions in schizophrenia. Dopamine D2 receptor partial agonists such as aripiprazole represent a treatment option for patients with this severe disorder. The ineffectiveness of terguride, another D2 receptor partial agonist, in treating schizophrenia was recently attributed to its considerably high intrinsic activity at D2 receptors. In this study, we used functional assays for recombinant D2 receptors and native 5-hydroxytryptamine 2A (5-HT2A), α2C-adrenergic, and histamine H1 receptors to compare the pharmacological properties of terguride and three of its halogenated derivatives (2-chloro-, 2-bromo-, 2-iodoterguride) with those of aripiprazole. Subsequently, we studied the antidopaminergic effects of 2-bromoterguride using amphetamine-induced locomotion (AIL). Its influence on spontaneous behavior was tested in the open field. Extrapyramidal side effect (EPS) liability was evaluated by catalepsy test. In a guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPγS) binding assay, 2-chloro-, 2-bromo-, and 2-iodoterguride produced intrinsic activities at human D2short (hD2S) receptors that were half as high as the intrinsic activity for terguride; aripiprazole lacked agonist activity. 2-Bromoterguride and aripiprazole activated D2S receptor-mediated inhibition of cAMP accumulation to the same extent; intrinsic activity was half as high as that of terguride. All compounds tested behaved as antagonists at human D2long/Gαo (hD2L/Gαo) receptors. Compared with aripiprazole, terguride and its derivatives displayed higher affinity at porcine 5-HT2A receptors and α2C-adrenoceptors and lower affinity at H1 receptors. 2-Bromoterguride inhibited AIL and did not induce catalepsy in rats. Because of its in vitro and in vivo properties, 2-bromoterguride may be a strong candidate for the treatment of schizophrenia with a lower risk to induce EPS.

Antispasmodic activity of essential oil from Lippia dulcis Trev.

AIM OF THIS STUDY: To investigate the essential oil of Lippia dulcis Trev. (Verbenaceae) that is traditionally used in the treatment of cough, colds, bronchitis, asthma, and colic in Middle America for antispasmodic activity. MATERIALS AND METHODS: We used a porcine bronchial bioassay to study contractile responses to carbachol and histamine in the absence or presence of the essential oil. RESULTS: The essential oil showed anti-histaminergic and anti-cholinergic activities at 100 microg/ml. CONCLUSIONS: The anti-histaminergic and anti-cholinergic activities of the essential oil of Lippia dulcis support the rational use of the plant or plant extracts to treat bronchospasm.

Pharmacological profile of the clonidine-induced inhibition of vasodepressor sensory outflow in pithed rats: correlation with alpha(2A/2C)-adrenoceptors.

BACKGROUND AND PURPOSE: Resistance blood vessels are innervated by sympathetic and primary sensory nerves, which modulate vascular tone through the release of noradrenaline and calcitonin gene-related peptide (CGRP), respectively. Moreover, electrical stimulation of the perivascular sensory outflow in pithed rats results in vasodepressor responses which are mainly mediated by CGRP release. The present study has investigated the role of alpha(2)-adrenoceptors in the inhibition of these vasodepressor responses. EXPERIMENTAL APPROACH: 144 pithed male Wistar rats were pretreated with hexamethonium (2 mg kg(-1) min(-1)) followed by i.v. continuous infusions of either methoxamine (15 and 30 microg kg(-1) min(-1)) or clonidine (3, 10 and 30 microg kg(-1) min(-1)). Under these conditions, electrical stimulation (0.56-5.6 Hz; 50 V and 2 ms) of the spinal cord (T(9)-T(12)) resulted in frequency-dependent decreases in diastolic blood pressure. KEY RESULTS: The infusion of clonidine (10 microg kg(-1) min(-1)), as compared to those of methoxamine (15 or 30 microg kg(-1) min(-1)), inhibited the vasodepressor responses to electrical stimulation without affecting those to i.v. bolus injections of alpha-CGRP (0.1-1 microg kg(-1)). This inhibition by clonidine was: (i) antagonized by 300 microg kg(-1) rauwolscine (alpha(2A/2B/2C)), 300 and 1000 microg kg(-1) BRL44408 (alpha(2A)), or 10 and 30 microg kg(-1) MK912 (alpha(2C)); and (ii) unaffected by 1 ml kg(-1) saline, 100 microg kg(-1) BRL44408, 3000 and 10,000 microg kg(-1) imiloxan (alpha(2B)) or 3 microg kg(-1) MK912. CONCLUSIONS AND IMPLICATIONS: The inhibition produced by 10 microg kg(-1) min(-1) clonidine on the vasodepressor (perivascular) sensory outflow in rats may be mainly mediated by prejunctional alpha(2A)/alpha(2C)-adrenoceptors.

Characterization of the postjunctional alpha 2C-adrenoceptor mediating vasoconstriction to UK14304 in porcine pulmonary veins.

BACKGROUND AND PURPOSE: In terms of postjunctional alpha(2)-adrenoceptors in the pulmonary circulation, no evidence is available with regard to the receptor subtypes mediating vasoconstriction. Therefore, we characterized the alpha(2)-adrenoceptor subtypes mediating contraction in isolated porcine pulmonary veins. EXPERIMENTAL APPROACH: alpha-adrenoceptor-mediated vasoconstriction was studied using a tissue bath protocol. mRNA profile and relative quantification of alpha(2)-adrenoceptor subtypes were determined in porcine pulmonary veins using reverse-transcriptase polymerase chain reaction (RT-PCR) and real-time PCR. KEY RESULTS: In porcine pulmonary veins, noradrenaline, phenylephrine (alpha(1)-adrenoceptor agonist), UK14304 and clonidine (alpha(2)-adrenoceptor agonists) caused concentration-dependent contractions. The rank order of agonist potency was: NA approximately UK14304 approximately clonidine > phenylephrine. UK14304 responses were antagonised by MK912 (noncompetitive antagonist parameter pD'(2): 10.1), rauwolscine (pK(B): 9.5), yohimbine (pK(B): 9.1), WB4101 (pK(B): 8.7), ARC239 (pK(B): 7.5), prazosin (pK(B): 7.1) and BRL44408 (pK(B): 7.0). Antagonist potencies fitted best with radioligand binding data (pK(i)) at the human recombinant alpha(2C)-adrenoceptor (r(2)=0.96, P=0.0001). Correlation with alpha(2B)-adrenoceptors was lower (r(2)=0.74, P>0.01) and no correlation was obtained with alpha(2A)-adrenoceptors. Moreover, RT-PCR studies in porcine pulmonary veins showed mRNA signals for alpha(2A)- and alpha(2C)-adrenoceptors, but not for alpha(2B)-adrenoceptors, whilst real-time PCR studies indicated a prominent expression of alpha(2C)-adrenoceptor mRNA. CONCLUSIONS AND IMPLICATIONS: Postjunctional alpha(2C)-adrenoceptors mediated contraction in porcine pulmonary veins. alpha(1)-Adrenoceptors also seem to be present in this tissue. Since alpha(2)-adrenoceptor responsiveness is increased when pulmonary vascular tone is elevated, alpha(2C)-adrenoceptor antagonists may be beneficial in diseases such as pulmonary hypertension or congestive heart failure.

Lisuride, a dopamine receptor agonist with 5-HT2B receptor antagonist properties: absence of cardiac valvulopathy adverse drug reaction reports supports the concept of a crucial role for 5-HT2B receptor agonism in cardiac valvular fibrosis.

OBJECTIVES: The high incidence of fibrotic cardiac valvulopathies reported in association with the 8beta-ergoline dopamine (DA) agonist, pergolide, and also case reports for cabergoline and bromocriptine have made it necessary to review the theoretical basis and actual findings in the case of another DA agonist, the 8alpha-ergoline lisuride (used since the 1970s for migraine prophylaxis as well as since the 1980s for its prolactin-lowering and anti-Parkinson activity). METHODS: We have reviewed the pharmacology of lisuride in relation to other DA agonists, and we have performed a throughout literature search as well as a search of our own and other adverse drug reaction databases for a possible relationship of lisuride with cardiac valvulopathy or for any reports of fibrosis in other locations. RESULTS: Our review of the pharmacology and the literature strongly suggests that drug-induced cardiac valvulopathies are always related to a stimulatory drug effect on trophic 5-HT(2B) receptors. As lisuride is devoid of such an effect, but on the contrary is an extremely potent 5-HT(2B) antagonist, an association of lisuride therapy with cardiac valvulopathies seems to be highly unlikely. In agreement with this hypothesis, not a single report of a cardiac valvulopathy associated with lisuride therapy has been identified in any database so far.Furthermore, against a background of an estimated 360,000 patient years, we have found only a very small number of cases of any other form of fibrosis (1x retroperitoneal, 2x pleural, 2x pulmonary, 1x interstitial pulmonary changes), in part combined with other risk factors and confounding variables. This closely matches 4 reports available from WHO (1x retroperitoneal, 3x pleural fibrosis). In addition, only 5 other possibly related conditions (3x pleural effusion, 1x pleuritis, 1x pericarditis) were identified in the lisuride adverse drug reaction database of Schering, Berlin. CONCLUSIONS: No link has been found between lisuride use and fibrotic cardiac valvulopathy, in agreement with the 5-HT(2B) receptor antagonist effect of this drug. The very low incidence of spontaneous reports of any other fibrosis could be even compatible with an association by chance in the population exposed to lisuride. Although close monitoring for this kind of side effects is still to be recommended in the therapy with lisuride, our data do not support the concept of a class effect suggesting that all ergot-derived drugs and especially DA receptor agonists with some chemical similarity to the ergot structure will cause or facilitate cardiac valvulopathies as observed with pergolide.

Proterguride, a highly potent dopamine receptor agonist promising for transdermal administration in Parkinson's disease: interactions with alpha(1)-, 5-HT(2)- and H(1)-receptors.

Dopamine receptor agonists play an important role in the treatment of Parkinson's disease and hyperprolactinemic conditions. Proterguride (n-propyldihydrolisuride) was already reported to be a highly potent dopamine receptor agonist, thus its action at different non-dopaminergic monoamine receptors, alpha(1A/1B/1D), 5-HT(2A/2B)- and histamine H(1), was investigated using different functional in vitro assays. The drug behaved as an antagonist at alpha(1)-adrenoceptors without the ability to discriminate between the subtypes (pA(2) values: alpha(1A) 7.31; alpha(1B) 7.37; alpha(1D) 7.35) and showed antagonistic properties at the histamine H(1) receptor. In contrast, at serotonergic receptors (5-HT(2A), 5-HT(2B)) proterguride acted as a partial agonist. The drug stimulated 5-HT(2A) receptors of rat tail artery in lower concentrations than 5-HT itself but failed to evoke comparable efficacy (proterguride: pEC(50) 8.34, E(max) 53% related to the maximum response to 5-HT; 5-HT: pEC(50) 7.03). Agonism at 5-HT(2B) receptors is presently considered to be involved in drug-induced valvular heart disease. Activation of 5-HT(2B) receptors in porcine pulmonary arteries by proterguride (pEC(50) 7.13, E(max) 49%; E(max) (5-HT) 69%), however, occurred at concentrations much higher than plasma concentrations achieving dopaminergic efficacy in humans. The results are discussed focussing on the relevance of action at 5-HT(2B) receptors as well as their significance for a transdermal administration of proterguride. Since it is well accepted that pulsatile dopaminergic stimulation is associated with treatment-related motor complications in the dopaminergic therapy of Parkinson's disease, the transdermal route of administration is of great clinical interest due to the possibility to achieve constant plasma concentrations.

Piperidine-containing histamine H3 receptor antagonists of the carbamate series: the alkyl derivatives.

A series of N-alkyl urethanes, potential histamine H3 receptor antagonists, was prepared. Carbamate derivatives were synthesized from appropriate isocyanates and N-piperidinoalkan-1-ols. The novel compounds were evaluated for histamine H3 receptor activity in vitro on the guinea pig ileum. Some selected compounds were tested in vivo after p.o. application to mice and in vitro for selectivity towards other histamine receptors (H1, H2) in functional assays in the guinea pig. The most potent H3 receptor antagonist in vitro was compound 14 (pA2 = 7.2). Compound 14 was equipotent at M3 receptors and lacked H3 receptor activity in vivo. Predictions of octanol-water partition coefficient (Pallas) and metabolic fate (MetabolExpert, METEOR) were used to explore potential reasons for this absence of in vivo activity.

Search for histamine H3 receptor antagonists with combined inhibitory potency at Ntau-methyltransferase: ether derivatives.

With the recent development of new hybrid compounds having histamine H3 receptor antagonist with combined histamine Ntau-methyltransferase (HMT) inhibitory potency an innovative approach was described in the research of novel lead compounds modulating histaminergic neurotransmission. Several compounds containing an ether moiety derived from the recently published 4-(3-piperidinopropoxy)phenylaminoquinoline derivatives (like FUB 836), were synthesized in this study and tested for their affinity at cloned human histamine H3 (hH3) receptors and on the inhibition of rat HMT. Besides different heterocycles, e.g. nitro- or amino-substituted pyridines, quinolines, benzothiazole or pyrroline, three classes of compounds were produced: heteroaromatic 3-piperidinopropyl ethers, keto- or imino-substituted 4-(3-piperidinopropyl)phenyl ethers and 4-(3-piperidinopropyl)phenyl ethers with substituted (alkyl)aminopyridines. Whereas the (3-piperidinopropoxy)heterocycles showed only moderate activities on both test models, the 4-(3-piperidinopropoxy)phenyl derivatives were identified as potent histamine H3 receptor ligands and/or HMT inhibitors. Ki values up to 0.42 nM were found for the affinity to the hH3 receptor. HMT inhibitory potency was identified with IC50 values about 0.3 microM for the most potent compounds in this series. Comparison of the pyridine-containing derivatives to recently published quinoline analogues showed a decrease in potencies for the pyridines. The dual activity, H3 receptor affinity and HMT inhibition, was moderate to good. For all compounds affinities at hH3 receptors were higher than their inhibitory HMT potencies. The described new histamine H3 receptor antagonists with an ether moiety represent a further promising step in our investigations for a dual activity.

Evidence for 5-HT2B and 5-HT7 receptor-mediated relaxation in pulmonary arteries of weaned pigs.

This study characterizes the relaxant response to 5-hydroxytryptamine (5-HT) in prostaglandin F(2alpha) (PGF(2alpha))-precontracted pulmonary arteries of weaned pigs. In arterial rings with intact endothelium, the relaxation to 5-HT was biphasic. The high affinity component of relaxation to 5-HT (0.1-10 nM) was abolished by mechanical removal of the endothelium or after the addition of L: -NAME (200 microM), and was inhibited by the 5-HT(2B/2C) receptor antagonist SB 206553 (1 microM), but not the 5-HT(2C) receptor antagonist SB 242084 (0.1 microM). Endothelium-intact arteries were also relaxed by the selective 5-HT(2B) receptor agonist BW 723C86 (pD(2) 7.7). The relaxant response to BW 723C86 was inhibited by 1 microM SB 206553 (pK(B) 6.8). The low affinity component of relaxation to 5-HT (>/=30 nM) remained unaffected after mechanical removal of the endothelium or the addition of L: -NAME. In endothelium-denuded arterial rings, 5-HT, 5-carboxamidotryptamine (5-CT), 5-methoxytryptamine (5-MeOT), and frovatriptan produced monophasic relaxations with pD(2) values of 6.5, 7.5, 5.9, and 4.7 respectively. Relaxant responses to the agonists were antagonized by the selective 5-HT(7) receptor antagonist SB 269970 (pK(B) 8.2-8.9). The relaxant response to the potent 5-HT(7) receptor agonist 5-CT was also antagonized by methiothepin (pK(B) 9.6), pimozide (pK(B) 8.2), mesulergine (pK(B) 7.7), methysergide (pK(B) 7.4), clozapine (pK(B) 7.6), and spiperone (pK(B) 7.4). The estimated pK(B) values argue in favor of an involvement of 5-HT(7) receptors in the direct vasorelaxant action of 5-HT in the pulmonary arteries of weaned pigs. The relaxant response to 5-CT was associated with an increase in cAMP that was surmountably antagonized by SB 269970 (pK(B) 8.6). The present in vitro bioassay can be used to characterize new drugs with potential agonist or antagonist properties at functional 5-HT(7) receptors.

Unexpected partial H1-receptor agonism of imidazole-type histamine H3-receptor antagonists lacking a basic side chain.

OBJECTIVE AND DESIGN: The putative partial H1-receptor agonism of some H3-receptor antagonists belonging to the proxifan series was characterized in a functional in-vitro assay using guinea-pig ileum. METHODS: Whole segments of guinea-pig ileum were mounted in Tyrode's solution under isotonic conditions in the presence of atropine (10(-7) M) and were cumulatively treated with histamine as an internal reference. After washout, the putative H1-receptor agonists were added cumulatively to determine agonist potency (pEC50) and intrinsic activity (Emax) relative to histamine. Maximal or supramaximal concentrations of partial agonists, or sufficient concentrations of H1-receptor antagonists were incubated for 3-15 min prior to construction of a second concentration-effect curve to histamine in order to calculate partial agonist or antagonist affinity for the H1 receptor (pKP or pA2 value, respectively). RESULTS: Several analogues of FUB 372 displayed low H1-receptor affinities (pA2 or pKP 4.2-5.5) except for a methyl benzoate derivative (pA2 = 6.81, Schild plot slope unity). FUB 372, four ortho-substituted derivatives (R = F, CH3, OCH3, CF3), and ciproxifan were weak contractile agents (Emax 9-38%, pEC50 4.73-5.68, histamine: 6.70) susceptible to antagonism by the H1-antihistaminergic drug mepyramine (2.10(-9)-10(-7) M). Agonist potency and H1-receptor affinity of these compounds did not correlate with the data of a set of H1-histaminergic 2-phenylhistamines bearing the same substituents. CONCLUSIONS: A specific subset of proxifans related to FUB 372 and ciproxifan represent a unique type of H1-receptor agonists lacking a basic side chain.

Involvement of 5-HT1B receptors in triptan-induced contractile responses in guinea-pig isolated iliac artery.

Using a series of triptans we characterized in vitro the 5-hydroxytryptamine (5-HT) receptor that mediates the contraction in guinea-pig iliac arteries moderately precontracted by prostaglandin F2alpha (PGF2alpha). Additionally, we investigated by reverse-transcriptase polymerase chain reaction (RT-PCR) which triptan-sensitive receptor is present in this tissue. Frovatriptan, zolmitriptan, rizatriptan, naratriptan, sumatriptan, and almotriptan contracted guinea-pig iliac arteries with pD2 values of 7.52+/-0.04, 6.72+/-0.03, 6.38+/-0.06, 6.22+/-0.05, 5.86+/-0.05 and 5.26+/-0.04 respectively. For comparison, the pD2 values for 5-HT and 5-carboxamidotryptamine (5-CT) were 7.52+/-0.02 and 7.55+/-0.03 respectively. In contrast to all other triptans tested, the concentration-response curve for eletriptan was biphasic (first phase: 0.01-3 microM, pD2 approximately 6.6; second phase: > or = 10 microM). Contractions to 5-HT, 5-CT, frovatriptan, zolmitriptan, rizatriptan, naratriptan, sumatriptan, almotriptan, and eletriptan (first phase) were antagonized by the 5-HT1B/1D receptor antagonist GR127935 (10 nM) and the 5-HT1B receptor antagonist SB216641 (10 nM). RT-PCR studies in guinea-pig iliac arteries showed a strong signal for the 5-HT1B receptor while expression of 5-HT1D and 5-HT1F receptors was not detected in any sample. The present results demonstrate that triptan-induced contraction in guinea-pig iliac arteries is mediated by the 5-HT1B receptor. The guinea-pig iliac artery may be used as a convenient in vitro model to study the (cardio)vascular side-effect potential of anti-migraine drugs of the triptan family.

Pergolide, terguride and N,N'-spacer-linked oligomers of both interact with 5-HT2A receptors of rat tail artery.

Pergolide, terguride and N,N'-spacer-linked oligomers of both have been tested for their ability to interact with 5 hydroxytryptamine(HT)2A receptors of rat tail artery. Pergolide was a potent partial agonist (pEC50 7.5, Emax 55 %) and antagonized 5-HT-induced contractions (pKp 7.2). Pergolide dimer 3 with a p-xylene spacer between the indole nitrogens (N-1) displayed somewhat lower agonist potency than pergolide (pEC50 7.0, Emax 55 %, pKp 6.6). The contractile responses to pergolide and dimer 3 were antagonized by the 5-HT2A receptor antagonist ketanserin (pA2 9.4, 9.1). In contrast to pergolide dimer 3, pergolide dimers 5 and 9 with an alkyl and an aralkyl spacer between the piperidine nitrogens (N-6) lacked agonism and displayed low affinity at 5-HT2A receptors (pA2 < 5.5). Terguride behaved as an insurmountable antagonist of 5-HT (pA2 8.4). Oligomers of terguride showed 5 to 50-fold lower affinity. It is concluded that pergolide and terguride show a high affinity for 5-HT2A receptors, but dimerization (oligomerization) of both drugs fails to increase affinity.

Main constituents of a commercial Drosera fluid extract and their antagonist activity at muscarinic M3 receptors in guinea-pig ileum.

The range of known constituents of Drosera species is extended by identification of myricetin 3-O-galactoside, from D. madagascariensis, and (+)-cis-isoshinanolone, obtained from a commercial fluid extract. They are accompanied by the naphthoquinones droserone and plumbagin, typical of this taxon, and a series of ubiquitous flavonols, including the rarely found gossypitrin present in the latter source. Conspicuously, the commercial form of D. peltata, non-accepted by the commission E, was found to be devoid of flavonoids. In addition, the fortuitous availability of the authentic enigmatic sample 'CON', previously isolated from D. rotundifolia, led to its characterization as common quercetin. Experiments performed on isolated guinea-pig ileum demonstrated that quercetin respectively 'CON' moderately inhibited carbachol-induced contractions at 10 microM (pD'2 5.09 +/- 0.02), while (+)-cis-isoshinanolone (100 microM) was inactive. This result indicates that quercetin derivatives may well contribute to the therapeutic use of Drosera preparations.

Piperidine-containing histamine H3 receptor antagonists of the carbamate series: the influence of the additional ether functionality.

Recently novel leads for histamine H3 receptor antagonists of the non-imidazole type have been described. As a continuation of this research eleven new carbamate derivatives possessing an additional ether functionality were prepared. The compounds were evaluated in vitro for their antagonist activity on isolated organs of guinea-pig (GP) H3 as well as H2, H1, and M3 receptors, respectively. All compounds investigated possessed moderate antagonist affinities at guinea-pig histamine H3 receptors (pA2 6.11-6.76). An ether functionality introduced in different places of the lipophilic part of carbamates differently influenced activity and selectivity toward H3, M3, and other histamine receptors tested.

Novel histaprodifen analogues as potent histamine H1-receptor agonists in the pithed and in the anaesthetized rat.

We have shown previously that histaprodifen and its Nalpha-substituted analogues methylhistaprodifen and dimethylhistaprodifen are highly potent H1-receptor agonists in vivo. The aim of the present study was to examine the influence of four newly synthesized histaprodifen analogues, 3-fluoro-methylhistaprodifen (1), Nalpha-imidazolylethylhistaprodifen (2), bis-histaprodifen (3) and Nalpha-methyl-bis-histaprodifen (4), on the cardiovascular system in the pithed and in the anaesthetized rat. In pithed and vagotomized rats, diastolic blood pressure (which was increased to 80-85 mmHg by vasopressin infusion) was decreased dose dependently by methylhistaprodifen (the reference compound) and by compounds 1-4. The maximum decrease was about 47-50 mmHg for methylhistaprodifen and compounds 1, 2 and 3. Their potencies, expressed as pED50 (the negative logarithm of the dose in mole per kilogram body weight that decreased diastolic blood pressure by 25 mmHg), were 8.31, 8.23, 8.26 and 7.84, respectively. With compound 4 the maximal effect was not achieved at doses up to 1 micromol/kg (the latter dose decreased blood pressure by about 30 mmHg; pED50 approximately 6.5). The vasodepressor effect of the five compounds was attenuated by the H1-receptor antagonist dimetindene (1 micromol/kg) but was not changed by combined administration of the H2- and H3-receptor antagonists ranitidine and thioperamide (1 micromol/kg each), by combined administration of the alpha1- and alpha2-adrenoceptor antagonists prazosin and rauwolscine (1 micromol/kg each) or by the beta-adrenoceptor antagonist propranolol (3 micromol/kg). In anaesthetized rats methylhistaprodifen and compounds 1-4 induced almost the same fall in blood pressure as in pithed and vagotomized animals; the effects were sensitive to blockade by dimetindene (1 micromol/kg). Higher doses of compounds 1 and 2 (1 micromol/kg) increased heart rate in pithed and vagotomized rats in a manner sensitive to propranolol (3 micromol/kg) but insensitive to dimetindene (3 micromol/kg). The same dose of methylhistaprodifen and of compounds 3 and 4 failed to affect heart rate. We conclude that the agonistic potency of compounds 1 and 2 at H1-receptors in the cardiovascular system of the rat equals that of methylhistaprodifen, the most potent histamine H1-receptor agonist available until recently. Compounds 1 and 2 exhibit sympathomimetic activity at high doses.

Complex interaction of ergovaline with 5-HT2A, 5-HT1B/1D, and alpha1 receptors in isolated arteries of rat and guinea pig.

Vascular effects of ergovaline mediated by 5-hydroxytryptamine(HT)2A, 5-HT1B/1D, and alpha1 receptors were studied in isolated arterial preparations of rat and guinea pig. In rat tail artery ergovaline behaved as a potent contractile partial agonist showing an agonist potency (pEC50) of 8.86 +/- 0.03, a maximum response (Emax) of 59 +/- 2% with respect to 5-HT, and a partial agonist affinity (pK(P)) of 8.51 +/- 0.06. Ergovaline was equipotent with ergotamine (pEC50, 8.69 +/- 0.07; Emax, 52 +/- 4%; pK(P), 8.36 +/- 0.11). Contractile responses to ergovaline and ergotamine were surmountably antagonized by the 5-HT2A receptor antagonist ketanserin (3 nM). Antagonist affinity (apparent pA2) for ketanserin against ergovaline and ergotamine was 9.19 +/- 0.08 and 9.36 +/- 0.17, respectively. Ergovaline showed extremely slow on-set and off-set kinetics in rat tail artery. The construction of cumulative concentration-response curves required about 4 h, and the contractile response to ergovaline (30 nM), which completely abolished the subsequent contractile response to 5-HT (10 nM to 1 mM), could not be reversed by wash-out. In guinea pig iliac artery moderately precontracted with prostaglandin F2alpha (0.05 to 0.5 microM) ergovaline behaved as an agonist (pEC50, 7.71 +/- 0.10) with a potency similar to that of 5-HT (pEC50, 7.60 +/- 0.05). The contractile response to ergovaline was inhibited by the 5-HT1B/1D receptor antagonist GR127935 (10 nM). The apparent pA2 value for GR127935 against ergovaline was 8.90 +/- 0.12. Ergovaline (10 nM) produced no contractile response in guinea pig iliac artery when added before the PGF2alpha-induced precontraction but caused insurmountable blockade of the contractile response to the 5-HT1B/1D receptor agonist 5-carboxamidotryptamine (5-CT). The apparent pA2 value for ergovaline against 5-CT was 8.56 +/- 0.18. In rat thoracic aorta ergovaline (2 microM) activated alpha1 adrenoceptors only with low efficacy (Emax, 12 +/- 3%) but surmountably antagonized norepinephrine-induced contractions with a pK(P) of 7.07 +/- 0.12. It is concluded that the powerful constrictor effect of ergovaline mediated by activation of vascular 5-HT2A and 5-HT1B/1D receptors may explain the vascular symptoms of fescue toxicosis observed in livestock grazing tall fescue pastures infected with the endophytic fungus Neotyphodium coenophialum.

Anti-inflammatory and spasmolytic activity of extracts from Droserae herba.

An ethanolic extract of Drosera madagascariensis inhibited human neutrophil elastase with an IC50 of 9.4 microg/ml. The naphthoquinones present in the extract were not responsible for this effect, but flavonoids like quercetin (IC50 0.8 microg/ml), hyperoside (IC50 0.15 microg/ml) and isoquercitrin (IC50 0.7 microg/ml) contributed to inhibition of the enzyme. In guinea-pig ileum the extract (0.5-1 mg/ml) induced a spasmolytic effect via affecting cholinergic M3 receptors and histamine H1 receptors, respectively. At contractile prostanoid receptors of guinea-pig trachea the Drosera extract was not effective.

Benzophenone derivatives and related compounds as potent histamine H3-receptor antagonists and potential PET/SPECT ligands.

Para-substituted aromatic ethers with benzophenone or related structural elements and a 3-(1H-imidazol-4-yl)propyloxy moiety were prepared by Mitsunobu-type ether synthesis or SNAr reaction. Most of the title compounds possess high antagonist potency in histamine H3-receptor assays in vitro as well as in vivo in mouse CNS following oral administration. After defining 4-(3-(1H-imidazol-4-yl)propyloxy)phenyl phenyl methanone as a new lead, structure-activity relationships were investigated for this new class of compounds. Substitution of the meta'-position of the benzophenone moiety with halogen atoms (e.g., iodine, fluorine) led to compounds with high antagonist potency in vitro as well as in vivo (Ki = 9.3 and 4.3 nM, ED50 = 0.7 and 0.47 mg/kg p.o., 18 and 12, respectively). A receptor profile of several functional in vitro assays for several biogenic amine receptors for the meta'-iodinated derivative demonstrated high selectivity toward the histamine H3 receptor.

Piperidine-containing histamine H3-receptor antagonists of the carbamate series: variation of the spacer length.

Ten carbamate derivatives have been prepared from appropriate isocyanates and omega-piperidino-1-alkanols. All compounds belong to the new generation of non-imidazole histamine H3-receptor ligands which may have beneficial pharmacokinetic properties compared with the classical imidazole-containing H3-receptor antagonists. The carbamates were evaluated in vitro for antagonist activity at guinea-pig (gp) H3, H2, H1, and M3 receptors, respectively. They displayed moderate affinity for H3 receptors (pA2 5.8-7.0 in the gp ileum assay) as well as low to moderate selectivities vis-à-vis H2 (gp atrium), H1 (gp ileum), and M3 (gp ileum) receptors. A typical member of this series is 7-piperidino-1-heptyl N-(4-phenyl-1-butyl)carbamate (17) with pA2 values of 7.02 (H3), 5.92 (H1), and 6.38 (M3), respectively, and a pD'2 value of 5.46 (H2).

New histamine H(3)-receptor ligands of the proxifan series: imoproxifan and other selective antagonists with high oral in vivo potency.

Histamine H(3)-receptor antagonists of the proxifan series are described. The novel compounds possess a 4-(3-(phenoxy)propyl)-1H-imidazole structure and various functional groups, e.g., an oxime moiety, on the phenyl ring. Synthesis of the novel compounds and X-ray crystallography of one highly potent oxime derivative, named imoproxifan (4-(3-(1H-imidazol-4-yl)propyloxy)phenylethanone oxime), are described. Most of the title compounds possess high antagonist potency in histamine H(3)-receptor assays in vitro as well as in vivo in mouse CNS following po administration. Structure-activity relationships are discussed. Imoproxifan displays subnanomolar potency on a functional assay on synaptosomes of rat cerebral cortex (K(i) = 0.26 nM). In vivo, imoproxifan increases the central N(tau)-methylhistamine level with an ED(50) of 0.034 mg/kg po. A receptor profile on several functional in vitro assays was determined for imoproxifan, demonstrating high selectivity toward the histamine H(3) receptor for this promising candidate for further development.