Novel 2-imidazoles as potent and selective alpha1A adrenoceptor partial agonists.

Novel 2-imidazoles have been identified as potent partial agonists of the alpha(1A) adrenergic receptor, with good selectivity over the alpha(1B), alpha(1D) and alpha(2A) receptor sub-types. Sulfonamide 23 possessed attractive drug-like properties with respect to physicochemical and ADME properties and wide ligand selectivity.

Structure-intrinsic activity relationship studies in the group of 1-imido/amido substituted 4-(4-arylpiperazin-1-yl)cyclohexane derivatives; new, potent 5-HT1A receptor agents with anxiolytic- like activity.

Introduction of 1,4-disubstituted cyclohexane ring in the structure of flexible long chain arylpiperazines resulted in linearly constrained, potent serotonin (5-HT)(1A) ligands. In order to trace structure-intrinsic activity relationships in this group, a new series of 1-substituted 4-(4-arylpiperazin-1-yl)cyclohexane derivatives with different cyclic imide/amide termini, and their flexible, tetramethylene analogues were synthesized and pharmacologically evaluated for 5-HT(1A) receptors. In vitro binding experiments revealed that all the compounds were potent 5-HT(1A) receptor agents (K(i) = 1.9-74 nM). Some derivatives tested additionally showed also high affinity for alpha(1)-adrenergic receptors (K(i) = 2.9-101 nM) and for 5-HT(7) receptors. Functional in vivo examination revealed that rigid ligands with o-OCH(3) group in the aryl moiety and cyclic imide system in the opposite terminal behaved like postsynaptic 5-HT(1A) receptor antagonists. On the other hand, unsubstituted, m-Cl, or m-CF(3) substituted derivatives as well as those with cyclic amide group in the terminal fragment exhibited agonistic or partial agonistic activity. Three out of four derivatives tested, that is, postsynaptic 5-HT(1A) antagonists 9 and 10, and partial agonist 16, showed anxiolytic-like activity in the conflict drinking (Vogel) test in rats.

Synthesis and development of new 2-substituted 1-[3-(4-arylpiperazin-1-yl)propyl]-pyrrolidin-2-one derivatives with antiarrhythmic, hypotensive, and alpha-adrenolytic activity.

A series of new 1-[3-(4-arylpiperazinyl-1-yl)-2-(N-alkylcarbamoyloxy)propyl]-pyrrolidin-2-one derivatives (4a-12a) were synthesised and tested for their electrocardiographic, antiarrhythmic and antihypertensive activity, as well as for the alpha1- and alpha2-adrenoceptor binding affinities. Of the newly synthesised derivatives, 1-{2-(N-2-methylethylcarbamoiloxy)-3-[4-(2-methoxyphenyl)piperazin-1-yl)]propyl}pyrrolidin-2-one dihydrochloride (10a) was the most active in prophylactic antiarrhythmic tests, its ED50 value equalling 2.7 mg kg(-1), and the therapeutic index being 75.2; moreover, compound 10a was also found to possess hypotensive activity. A preliminary molecular modelling study suggested that the selected alpha1-AR antagonist distances and angles between pharmacophoric features, estimated for the tested compounds, were in good agreement with the parameters evaluated for ligands.

[Synthesis of BODIPY-FL-labeled phenylephrine and the determination of its biological activity].

OBJECTIVE: To synthesize BODIPY-FL-labeled phenylephrine (BODIPY-FL-PE) and determine its biological activity. METHODS: Condensation of BODIPY-FL (green fluorescence dye) and phenylephrine (alpha1-adrenoceptor agonist) was performed by adding dicyclohexylcarbodiimide (DCC) in the presence of absolute tetrahydrofuran(THF). The reaction occurred in absolutely oxygen and water condition at room temperature. The crude product was separated and purified by thin-layer chromatography (TLC). The structure of BODIPY-FL-PE was characterized by TLC and mass spectrometry (MS). Its pharmabiological activity was determined by Western blot. RESULTS: BODIPY-FL-PE,the target molecule, was synthesized and its structure was identified by using ultra-violet spectrometry (UV) and MS. The result of Western blot indicated that alpha1-adrenoceptor (alpha1-AR) induced ERK phosphorylation was confirmed in both BODIPY-FL-PE and PE treated groups. CONCLUSION: The synthesized BODIPY-FL-PE has pharmacological activity that could activate alpha1-AR. Visualization of AR behaviors could be achieved by tracing the trajectories of BODIPY-FL-PE labeled AR. It might be a promising tool for investigating dynamic behaviors of AR in living cells.

seco-C/D ring analogues of ergot alkaloids. Synthesis via intramolecular Heck and ring-closing metathesis reactions.

[reaction: see text] Intramolecular Heck and ring-closing metathesis reactions on key intermediates 10 and 15, respectively, provide efficient entries into seco-C/D ring analogues of Ergot alkaloids 12 and 16, compounds of potential synthetic and biological interest.

Synthesis and structure-affinity relationship investigations of 5-aminomethyl and 5-carbamoyl analogues of the antipsychotic sertindole. A new class of selective alpha1 adrenoceptor antagonists.

A new class of selective alpha(1) adrenoceptor antagonists derived from the antipsychotic drug sertindole is described. The most potent and selective compound 1-(2-(4-[5-aminomethyl-1-(4-fluorophenyl)-1H-indol-3-yl]-1-piperidinyl)ethyl)-2-imidazolidinone (11) binds with 0.50 nM affinity for alpha(1) adrenergic receptors and with more than 44 times lower affinity for dopamine D(2),D(3), D(4) and serotonin 5-HT(1A), 5-HT(1B), 5-HT(2A) and 5-HT(2C) receptors. The molecular features providing high affinity for adrenergic alpha(1) receptors and high selectivity towards dopamine D(2) and serotonin 5-HT(2A) and 5-HT(2C) receptors are discussed.

2-(Anilinomethyl)imidazolines as alpha1 adrenergic receptor agonists: alpha1a subtype selective 2'-heteroaryl compounds.

The structure-activity relationship of 2'-pyrrole, pyrazole and triazole substituted 2-(anilinomethyl)imidazolines as alpha(1) adrenergic agonists was investigated. The size and orientation of substituents, as well as the position of the heteroatoms, were found to have a profound effect on the potency and selectivity of the molecules. Potent alpha(1A) subtype selective agonists have been identified.

N-[3-(1H-imidazol-4-ylmethyl)phenyl]ethanesulfonamide (ABT-866, 1),(1) a novel alpha(1)-adrenoceptor ligand with an enhanced in vitro and in vivo profile relative to phenylpropanolamine and midodrine.

N-[3-(1H-Imidazol-4-ylmethyl)phenyl]ethanesulfonamide (ABT-866, 1) is a novel alpha(1) agent having the unique profile of alpha(1A) (rabbit urethra, EC(50) = 0.60 microM) agonism with alpha(1B) (rat spleen, pA(2) = 5.4) and alpha(1D) (rat aorta, pA(2) = 6.2) antagonism. An in vivo dog model showed 1 to be more selective for the urethra over the vasculature than A-61603 (2), ST-1059 (3, the active metabolite of midodrine), and phenylpropanolamine (4).

2-(Anilinomethyl)imidazolines as alpha1 adrenergic receptor agonists: the discovery of alpha1a subtype selective 2'-alkylsulfonyl-substituted analogues.

A series of 2'-alkylthio-2-(anilinomethyl)imidazolines were prepared to examine the effect of the alkyl group size, sulfur oxidation state, and phenyl ring substitution on ligand binding and agonism of alpha-adrenergic receptor subtypes alpha1a, alpha1b, alpha1d, alpha2a, and alpha2c. Binding at all receptor subtypes decreased for compounds in the sulfone oxidation state as compared to their sulfide analogues. While sulfides were generally potent, nonselective agonists, sulfones exhibited alpha1a subtype selectivity in a cell-based functional assay. Sulfone (32) was 250-7000-fold selective for alpha1a vs all other subtypes.

2-(anilinomethyl)imidazolines as alpha1A adrenergic receptor agonists: 2'-heteroaryl and 2'-oxime ether series.

A series of 2'-heteroaryl and 2'-oxime anilinomethylimidazolines was prepared and evaluated in in vitro functional assays for cloned human alpha1A, alpha1B, and alpha1D receptor subtypes. Potent and selective alpha1A agonists have been identified in these series.

Alpha2-adrenoreceptors profile modulation and high antinociceptive activity of (S)-(-)-2-[1-(biphenyl-2-yloxy)ethyl]-4,5-dihydro-1H-imidazole.

A number of derivatives structurally related to cirazoline (1) were synthesized and studied with the purpose of modulating alpha2-adrenoreceptors selectivity versus both alpha1-adrenoreceptors and I2 imidazoline binding sites. The most potent alpha2-agonist was 2-[1-(biphenyl-2-yloxy)ethyl]-4,5-dihydro-1H-imidazole (7), whose key pharmacophoric features closely matched those found in the alpha2-agonist 2-(3-exo-(3-phenylprop-1-yl)-2-exo-norbornyl)amino-2-oxazoline (15). (S)-(-)-7 was the most potent of the two enantiomers, confirming the stereospecificity of the interaction with alpha2-adrenoreceptors. This eutomer was tested on two algesiometric paradigms and, because of the interaction with alpha2-adrenoreceptors, showed a potent and long-lasting antinociceptive activity, since it was abolished by the selective alpha2-antagonist RX821002.

[(11)C]-GR89696, a potent kappa opiate receptor radioligand; in vivo binding of the R and S enantiomers.

The R and S enantiomers of [(11)C]GR89696, [(11)C]-methyl 4-[(3,4-dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate, were synthesized from their appropriate chiral precursors and [(11)C]methyl chloroformate. The [(11)C]-labeled R enantiomer of GR89696, also known as GR103545, demonstrated high affinity in mouse brain with region to cerebellar ratios at 90 minutes of 11.4 and 8.7 for the hypothalamus and olfactory tubercle, respectively. The [(11)C]-labeled S enantiomer showed low affinity and region to cerebellar ratios of 1 for all brain regions. The [(11)C]-labeled GR103545 exhibited a selective and saturable binding for the kappa opioid receptor.

Synthesis and stereoselective kappa-receptor binding of methylated analogues of GR-89.696.

Stereoselective synthesis of all four stereoisomers of methylated analogues 8 of the kappa-receptor agonist GR-89.696 is presented. Starting with orthogonally protected piperazine derivatives (R,R)-4 and (S,S)-4, the reaction sequence involves oxidation, reductive amination and modification of the piperazine nitrogen protective groups. The configuration of the stereocentre in alpha-position to the pyrrolidine moiety is determined by X-ray structure analysis of (R,S)-8. In receptor-binding studies with the radioligand U-69.593, the stereoisomer with (S)-configuration at both stereogenic centres (S,S)-8 displayed the highest kappa-receptor affinity with a K(i)-value of 0.67 nM.

Alpha(2) adrenoceptor agonists as potential analgesic agents. 3. Imidazolylmethylthiophenes.

A series of imidazolylmethylthiophenes has been prepared and evaluated as ligands for the alpha(2) adrenoceptor. These compounds were tested in two animal models that are predictive of analgesic activity in humans. The 3-thienyl compounds were generally the most potent, particularly those with substitution in the 4-position. A subset of the most active compounds was further evaluated for adverse cardiovascular effects in the anesthetized rat model. In addition to excellent binding at the alpha(2D) adrenoceptor, the 4-bromo analogues 20e and 21e were very active in the rat abdominal irritant test (RAIT) with ED(50) doses of 0.38 and 0.31 mg/kg, respectively. We constructed a pharmacophore model based on the biological activity of the present series, dexmedetomidine (1), and conformationally restrained analogues 3 and 4.

Synthesis and alpha(1)-antagonist activity of derivatives of 4-chloro-5-[4-[2-(2-methoxyphenoxy)-ethyl]-1-piperazinyl]-3(2H)-pyrid azinone.

The synthesis and evaluation of the biological activity of new 4-chloro-5-¿4-[2-(2-methoxyphenoxy)-ethyl]-1-piperazinyl¿-3(2H)-pyrid azinone derivatives are reported. The blocking activity of these compounds was determined on the pre- and postsynaptic alpha-adrenoceptors of isolated rat vas deferens.

2-amino-2-oxazolines as subtype selective alpha(2) adrenoceptor agonists.

Cyclohexylamino oxazoline 1 (AGN 190837), an analogue of 2 (Bay a6781), is a potent alpha(2) adrenoceptor agonist. On the basis of a design generated by receptor-ligand modeling, a number of cyclohexyl and norbornyl analogues were synthesized wherein the propyl group of 1 was replaced by phenylalkyl subsituents. This resulted in compound 6 being an alpha(2c) selective agonist, as well as 7 and 9 being alpha(2a)/alpha(2c) selective.

Synthesis and alpha-adrenergic binding ligand affinities of 2-iminoimidazolidine derivatives.

In order to obtain possible veinotonic drugs acting through alpha2 receptor activation, we prepared clonidine analogues in which the 2-imino-imidazolidine was attached to various aliphatic or aromatic heterocycles. Among them, the two benzopyranic derivatives 16 and 22 exhibited interesting affinities (19 and 95 nM respectively on [3H]rauwolscine binding, compared to 35 nM for clonidine). Their affinity for alpha1 receptors was found to be much lower: 7570 and 5030 nM for 16 and 22 respectively, suggesting 16 to be 400 times more selective for alpha2 than for alpha1-adrenoceptors.

WB 4101-related compounds. 2. Role of the ethylene chain separating amine and phenoxy units on the affinity for alpha(1)-adrenoreceptor subtypes and 5-HT(1A) receptors.

WB 4101 (1)-related benzodioxanes were synthesized by replacing the ethylene chain separating the amine and the phenoxy units of 1 with a cyclopentanol moiety, a feature of 6, 7-dihydro-5-[[(cis-2-hydroxy-trans-3-phenoxycyclopentyl)amino]meth yl] -2-methylbenzo[b]thiophen-4(5H)-one that was reported to display an intriguing selectivity profile at alpha(1)-adrenoreceptors. This synthesis strategy led to 4 out of 16 possible stereoisomers, which were isolated in the case of (-)-3, (+)-3, (-)-4, and (+)-4 and whose absolute configuration was assigned using a chiral building block for the synthesis of (-)-3 starting from (+)-(2R)-2, 3-dihydro-1,4-benzodioxine-2-carboxylic acid ((+)-9) and (1S,2S, 5S)-2-amino-5-phenoxycyclopentan-1-ol ((+)-10). The aim of this project was to further investigate whether it is possible to differentiate between these compounds with respect to their affinity for alpha(1)-adrenoreceptor subtypes and the affinity for 5-HT(1A) receptors, as 1 binds with high affinity at both receptor systems. The biological profiles of reported compounds at alpha(1)-adrenoreceptor subtypes were assessed by functional experiments in isolated rat vas deferens (alpha(1A)), spleen (alpha(1B)), and aorta (alpha(1D)) and by binding assays in CHO and HeLa cells membranes expressing the human cloned alpha(1)-adrenoreceptor subtypes and 5-HT(1A) receptors, respectively. Furthermore, the functional activity of (-)-3, (+)-3, (-)-4, and (+)-4 toward 5-HT(1A) receptors was evaluated by determining the induced stimulation of [(35)S]GTPgammaS binding in cell membranes from HeLa cells transfected with human cloned 5-HT(1A) receptors. The configuration of the cyclopentane unit determined the affinity profile: a 1R configuration, as in (+)-3 and (-)-4, conferred higher affinity at alpha(1)-adrenoreceptors, whereas a 1S configuration, as in (-)-3 and (+)-4, produced higher affinity for 5-HT(1A) receptors. For the enantiomers (+)-4 and (-)-4 also a remarkable selectivity was achieved. Functionally, the stereoisomers displayed a similar alpha(1)-selectivity profile, that is alpha(1D) > alpha(1B) > alpha(1A), which is different from that exhibited by the reference compound 1. The epimers (-)-3 and (+)-4 proved to be agonists at the 5-HT(1A) receptors, with a potency comparable to that of 5-hydroxytryptamine.