Effects of iodoproxyfan,a potent and selective histamine H3 receptor antagonist,onα 2 and 5-HT3 receptors

We determined the affinity and/or potency of the novel H₃ receptor antagonist iodoproxyfan at ₂ and 5-HT₃ receptors. Iodoproxyfan and rauwolscine (a reference ₂ ligand) (i) monophasically displaced³H-rauwolscine binding to rat brain cortex membranes (pK_i 6.79 and 8.59); (ii) facilitated the electrically evoked tritium overflow from superfused mouse brain cortex slices preincubated with³H-noradrenaline (pEC₅₀ 6.46 and 7.91) and (iii) produced rightward shifts of the concentration-response curve (CRC) of (unlabelled) noradrenaline for its inhibitory effect on the evoked overflow (pA₂ 6.65 and 7.88). In the guinea-pig ileum, iodoproxyfan 6.3µmol/l failed to evoke a contraction by itself but depressed the maximum of the CRC of 5-hydroxytryptamine (pD₂ 5.24). Tropisetron (a reference 5-HT₃ antagonist) produced rightward shifts of the CRC of 5-hydroxytryptamine (pA₂ 7.84). In conclusion, the affinity/potency of iodoproxyfan at H₃ receptors (range 8.3-9.7 [1]) exceeds that at ₂ receptors by at least 1.5 log units and that at 5-HT₃ receptors by at least 3 log units.     

α2-Adrenoceptors are targets for antipsychotic drugs

Rationale

Almost all antipsychotic drugs (APDs), irrespective of whether they belong to the first-generation (e.g. haloperidol) or second-generation (e.g. clozapine), are dopamine D₂ receptor antagonists. Second-generation APDs, which differ from first-generation APDs in possessing a lower propensity to induce extrapyramidal side effects, target a variety of monoamine receptors such as serotonin (5-hydroxytryptamine) receptors (e.g. 5-HT_1A, 5-HT_2A, 5-HT_2C, 5-HT₆, 5-HT₇) and α₁- and α₂-adrenoceptors in addition to their antagonist effects at D₂ receptors.

Objective

This short review is focussed on the potential role of α₂-adrenoceptors in the antipsychotic therapy.

Results

Schizophrenia is characterised by three categories of symptoms: positive symptoms, negative symptoms and cognitive deficits. α₂-Adrenoceptors are classified into three distinct subtypes in mammals, α_2A, α_2B and α_2C. Whereas the α_2B-adrenoceptor seems to play only a minor role in the brain, activation of postsynaptic α_2A-adrenoceptors in the prefrontal cortex improves cognitive functions. Preclinical models such as D-amphetamine-induced locomotion, the conditioned avoidance response and the pharmacological N-methyl-d-aspartate receptor hypofunction model have shown that α_2C-adrenoceptor blockade or the combination of D₂ receptor antagonists with idazoxan (α_2A/2C-adrenoceptor antagonist) could be useful in schizophrenia. A potential benefit of a treatment combination of first-generation APDs with the α_2A/2C-adrenoceptor antagonists idazoxan or mirtazapine was also demonstrated in patients with schizophrenia.

Conclusions

It is concluded that α₂-adrenoceptors may be promising targets in the antipsychotic therapy.     

Complete response to therapy: why do primary central nervous system lymphoma patients not return to work?

Journal of Neuro-Oncology - Evidence supporting routine postoperative antiepileptic drug (AED) prophylaxis following oncologic neurosurgery is limited, and actual practice patterns are largely...     

Development of a new class of nonimidazole histamine H(3) receptor ligands with combined inhibitory histamine N-methyltransferase activity

In search of novel ways to enhance histaminergic neurotransmission in the central nervous system, a new class of nonimidazole histamine H(3) receptor ligands were developed that simultaneously possess strong inhibitory activity on the main histamine metabolizing enzyme, histamine N-methyltransferase (HMT). The novel compounds contain an aminoquinoline moiety, which is an important structural feature for HMT inhibitory activity, connected by different spacers to a piperidino group (for H(3) receptor antagonism). Variation of the spacer structure provides two different series of compounds. One series, having only an alkylene spacer between the basic centers, led to highly potent HMT inhibitors with moderate to high affinity at human histamine H(3) receptors. The second series possesses a p-phenoxypropyl spacer, which may be extended by another alkylene chain. This latter series also showed strong inhibitory activity on HMT, and in most cases, the H(3) receptor affinity even surpassed that of the first series. One of the most potent compounds with this dual mode of action is 4-(4-(3-piperidinopropoxy)phenylamino)quinoline (34) (hH(3), K(i) = 0.09 nM; HMT, IC(50) = 51 nM). This class of compounds showed high antagonist potency and good H(3) receptor selectivity in functional assays in guinea pig on H(1), H(2), and H(3) receptors. Because of low or missing in vivo activity of two selected compounds, the proof of concept of these valuable pharmacological tools for the supposed superior overall enhancing effect on histaminergic neurotransmission failed to appear hitherto.     

Evidence that alpha(1B)-adrenoceptors are involved in noradrenaline-induced contractions of rat tail artery

The present study characterizes the alpha(1)-adrenoceptor subtypes mediating contractions to noradrenaline in isolated ring preparations of rat tail artery. Concentration-response (E/[A]) curves to noradrenaline were apparently monophasic (pEC(50) 6.47) but became biphasic in the presence of the selective alpha(1A)-adrenoceptor antagonist (+/-)-1,3,5-trimethyl-6-[[3-[4-((2,3-dihydro-2-hydroxymethyl)-1,4-benzodioxin-5-yl)-1-piperazinyl]propyl]amino]-2,4(1H,3H)-pyrimidinedione (B8805-033). Whereas the first phase of contraction to noradrenaline remained nearly unaffected in the presence of B8805-033 (0.03-3 microM), the second phase was concentration-dependently shifted to the right (pK(B) 8.06). In the presence of B8805-033 (3 microM), noradrenaline-induced contractions (pEC(50) 6.55) were antagonized in a competitive manner by prazosin (pK(B) 9.24), tamsulosin (pK(B) 8.55), 2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane (WB 4101; pK(B) 7.81), spiperone (pK(B) 7.69), 4-amino-2-[4-[1-(benzyloxycarbonyl)-2(S)-[[(1,1-dimethylethyl)amino]carbonyl]-piperazinyl]-6,7-dimethoxyquinazoline (L-765,314; pK(B) 7.31), 5-methylurapidil (pK(B) 6.55), 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione (BMY 7378; pK(B) 6.43), and 8-[2-(1,4-benzodioxan-2-ylmethylamino)ethyl]-8-azaspiro[4.5]decane-7,9-dione (MDL 73005EF; pK(B) 5.71), and were also antagonized by 100 microM chloroethylclonidine. N-[2-(2-cyclopropylmethoxyphenoxy)ethyl]-5-chloro-alpha,alpha-dimethyl-1H-indole-3-ethanamine (RS-17053) behaved as a noncompetitive antagonist (apparent pA(2) 6.55). Antagonist affinities obtained under these experimental conditions correlated highly with affinities at native and cloned alpha(1B)-adrenoceptors. Pretreatment of arterial rings with B8805-033 (3 microM) followed by receptor inactivation with chloroethylclonidine (100 microM) yielded monophasic E/[A] curves to noradrenaline (pEC(50) 6.14). Noradrenaline-induced contractions were competitively antagonized by tamsulosin (pK(B) 10.32), 5-methylurapidil (pK(B) 8.66), RS-17053 (pK(B) 8.44), B8805-033 (pK(B) 7.87), BMY 7378 (pK(B) 6.54), and L-765,314 (pK(B) 6.41). Antagonist affinities obtained under these experimental conditions correlated highly with affinities at native and cloned alpha(1A)-adrenoceptors. It is concluded that the contraction to noradrenaline in rat tail artery is mediated by both alpha(1B)- and alpha(1A)-adrenoceptors, each component of contraction being separable by use of selective alpha(1A)-adrenoceptor blockade and alpha(1B)-adrenoceptor alkylation, respectively.     

Structure-activity relationships of histamine H1-receptor agonists

Significant progress in the development of potent and selective histamine H1-receptor agonists has been achieved since 1990. Optimisation of the class of 2-phenylhistamines has furnished 2-[3-(trifluoromethyl)phenyl]histamine and its Nalpha-methyl derivative. The discovery of histaprodifen (2-[2-(3,3-diphenylpropyl)-1H-imidazol-4-yl]ethanamine) and the novel lead compound suprahistaprodifen (Nalpha-2-[(1H-imidazol-4-yl)ethyl]histaprodifen) represents additional milestones in the H1-receptor agonist field.     

New antithrombotic 1-phthalazinamines with serotonin antagonistic properties

We report nineteen 4-aryl- and 4-arylalkyl-1-phthalazinamines (5-8) which we prepared and tested for antithrombotic properties. All compounds were assayed for their antiplatelet activity in the "Born test" with collagen as inducer of the aggregation. N-[4-(1H-1, 2, 4-triazol-1-yl)butyl]-4-phenyl-1-phthalazin-amine (7 c) was the most potent compound, having an IC(50) of 8 microM. When 5-HT (Serotonin) was used to start aggregation the N-(furan-2-yl-methyl)-4-phenyl-1-pthtalazinamine (8 a) had an IC(50) of 2 microM. In vivo potencies were highly significant. N-[5-(1H-1, 2, 4-triazol-1-yl)pentyl]-4-phenyl-1-phthalazinamine (7 d) inhibited thrombus formation by 12% (P < 0.002) in arterioles and 7% (P < 0.01) in venoles as tested with our laser thrombosis model. For compound 8 a we surprisingly found an antagonism to the 5HT(2A) receptor, which is most likely the mechanism of the inhibition of aggregation by this compound.     

Characterization of the relaxant response to N,N'-dipropyl-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine in porcine coronary arteries

N,N'-Dialkyl-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamines show structural analogy with estrogens and selective estrogen receptor modulators. Because the vasodilator properties of these compounds are unknown, we investigated their potential to relax porcine coronary arteries and determined the mechanism(s) of relaxation. Isolated porcine coronary arterial rings were suspended in organ chambers, precontracted with KCl (30 mM), and the relaxant response was determined by measurement of changes in isometric force. Dependent on the chemical structure, the drugs induced concentration-dependent relaxation in rings with and without endothelium. N,N'-Dipropyl-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine (8) was most potent and showed a 12- to 15-fold higher vasodilatory effect than 17beta-estradiol (E2). The vasorelaxation was independent of endothelium. Calcium concentration-dependent contractions in high-potassium depolarizing medium were insurmountably inhibited by 8. The effect of the L-type Ca2+ channel activator (S)-(-)-Bay K 8644 [(S)-(-)-1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-3-pyridine-carboxylic acid methyl ester], which induced a leftward shift of Ca2+ contraction, was blocked by 8. The relaxant response to 8 was unaffected by the estrogen receptor antagonist ICI 182,780 (7alpha-[9-[(4,4,5,5,5-pentafluoropentyl]-sulfinyl]nonyl]-estra-1,3,5(10)-triene-3,17beta-diol) and K+ channel blockers, i.e., TEA, glibenclamide, and 4-aminopyridine. Furthermore, the vasodilatory effect of 8 was unaffected by the adenylyl cyclase inhibitor SQ 22536 [9-(tetrahydro-2-furanyl)-9H-purin-6-amine], the guanylyl cyclase inhibitor ODQ [1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one], the protein kinase A inhibitor KT 5720 [(9S,10S,12R)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg: 3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid hexyl ester], the protein kinase G inhibitor KT 5823 [(9S,10R,12R)-2,3,9,10,11,12-hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid methyl ester], and the p38 mitogen-activated protein kinase (MAPK) inhibitor SB 203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole]. Western blot analysis demonstrated that 8, unlike E2, raloxifene, and tamoxifen, failed to stimulate p38 MAPK. It is concluded that N,N'-dipropyl-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine induces endothelium-independent relaxation of coronary arteries; the mechanism apparently involves inhibition of L-type Ca2+ channels. The drug may be protective against cardiovascular diseases.     

Characterization of the molecular fragment that is responsible for agonism of pergolide at serotonin 5-Hydroxytryptamine2B and 5-Hydroxytryptamine2A receptors

Cardiac-valve regurgitation observed in Parkinson patients treated with the ergoline dopamine receptor agonist 8beta-methylthiomethyl-6-propylergoline (pergolide) has been associated with the agonist efficacy of the drug at 5-hydroxytryptamine(2B) (5-HT(2B)) receptors. 5-HT(2A) receptors may also play a role in pergolide-induced cardiac-valve regurgitation. We studied the pharmacological profile of pergolide and eight derivatives in porcine vascular rings endowed with 5-HT(2B) and 5-HT(2A) receptors to detect the molecular fragment of the pergolide molecule that may be responsible for agonism at these receptors. Pergolide derivatives showed a different substitution pattern at N(6), and the side chain at C(8) was modified by replacement of the sulfur against an oxygen atom. We demonstrate that the potent agonism of pergolide both at 5-HT(2B) and 5-HT(2A) receptors is retained when the N(6) propyl substituent is replaced by ethyl. However, agonism can be converted into antagonism if N(6) propyl is replaced by methyl. The N(6)-unsubstituted derivative was a low efficacy 5-HT(2B) receptor partial agonist and a 5-HT(2A) receptor antagonist. This pharmacological pattern was also applicable for pergolide congeners with an oxygen in the side chain at C(8). 6-Methylpergolide retained agonist efficacy and potency compared with pergolide at human (h) D(2LONG(L)) and hD(2SHORT(S)) receptors as determined by guanosine 5'-O-(3-[(35)S]thio)triphosphate binding. Based on the ability of pergolide to produce potent agonism at 5-HT(2B) receptors and the failure of 6-methylpergolide to act as an agonist but as a potent antagonist, we conclude that the N(6) propyl substituent of pergolide is crucial for 5-HT(2B) receptor agonism and thus a determinant of valvular regurgitation.     

Mutagenicity experiments on agroclavines, new natural antineoplastic compounds

Agroclavine, an alkaloid produced by some species of fungi and dicotyledon plants, and its 1-alkylated derivatives are potentially useful as antineoplastic drugs, since they exert potent and selective cytostatic effects. In the present study, we have investigated agroclavine and its 1-propyl and 1-pentyl derivatives for mutagenicity. The genetic end point studied was the reversion of strains of Salmonella typhimurium (TA 100, TA 98, TA 1537) and Escherichia coli (WP2 uvrA), auxotrophic for histidine and tryptophan, respectively. The compounds were tested directly and in the presence of a mammalian xenobiotic-metabolizing system. In the direct test, agroclavine and the two alkylated derivatives examined exhibited substantial bacteriotoxicity but no mutagenicity. Addition of NADPH-fortified postmitochondrial supernatant fraction of rat liver homogenate led to a clear-cut decrease in bacteriotoxicity and to the formation of mutagenic products. Each compound was effective in all three strains of S. typhimurium used. In E. coli only spurious effects were seen. 1-Pentylagroclavine, the most hydrophobic compound in the series, was the strongest mutagen. Agroclavine, the least hydrophobic compound, was the weakest. The mutagenic potencies and efficacies of all these test compounds were much weaker than those of the positive controls, which were known mutagens and carcinogens. Moreover, the differential effect of metabolism by liver enzymes demonstrates that the toxicity and mutagenicity of agroclavine and its derivatives are caused by different chemical species. Hence, it may be possible to develop derivatives that are cytotoxic but not mutagenic.