Synthesis and pharmacology of 3,4-dihydro-3-oxo-1,4-benzoxazine-8-carboxamide derivatives, a new class of potent serotonin-3 (5-HT3) receptor antagonists.

A series of 3,4-dihydro-3-oxo-1,4-benzoxazine-8-carboxamide derivatives was synthesized and evaluated for serotonin-3 (5-HT3) receptor antagonistic activity assessed by their ability to antagonize the von Bezold-Jarish (BJ) effect in rats. Derivatives bearing 1-azabicyclo[2.2.2]oct-3-yl moiety as a basic function attached to the carboxamide at position 8 showed more potent antagonistic activity than those bearing the other three basic moieties. Structure-activity relationships of this series showed that methyl and chloro groups were more effective as substituents at positions 4 and 6, respectively. The representative compound 15 (Y-25130) in this series showed potent antagonistic activity on the BJ effect (ED50 = 1.3 micrograms/kg i.v.), high affinity for 5-HT3 receptor (Ki = 2.9 nM) and complete protection against cisplatin-induced emesis in dogs at a dose of 0.1 mg/kg i.v.     

Synthesis and structure-activity relationships of 4-amino-5-chloro-N-(1,4-dialkylhexahydro-1,4-diazepin-6-yl)-2-methoxybenzamide derivatives,novel and potent serotonin 5-HT3 and dopamine D2 receptors dual antagonist

In search of a dopamine D2 and serotonin 5-HT3 receptors dual antagonist as a potential broad antiemetic agent, a number of benzamides were prepared from 4-amino-5-chloro-2-methoxybenzoic acid derivatives and 6-amino-1,4-dialkylhexahydro-1,4-diazepines and evaluated for their binding affinity for the dopamine D2 and the serotonin 5-HT3 receptors using rat brain synaptic and rat cortical membranes, respectively. From the results of both in vitro receptor binding and in vivo biological assays for the dopamine D2 receptor, 1-ethyl-4-methylhexahydro-1,4-diazepine ring was selected as an optimum amine moiety. Introduction of one methyl group on the nitrogen atom at the 4-position and/or modification of the substituent at the 5-position of the 4-amino-5-chloro-2-methoxybenzoyl moiety caused a marked increase in the dopamine D2 receptor binding affinity along with a potent 5-HT3 receptor binding affinity. Among the compounds, 5-chloro-N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)-2-methoxy-4-methylaminobenzamide (82), 5-bromo (110), and 5-iodo (112) analogues exhibited a much higher affinity for the dopamine D2 receptor than that of metoclopramide (IC50=17.5-61.0 nM vs. 483 nM). In particular, 82 showed a potent antagonistic activity for both receptors in vivo tests. Optical resolution of the racemate 82 brought about a dramatic change in the pharmacological profile with the (R)-enantiomer exhibiting a strong affinity for both the dopamine D2 and the 5-HT3 receptors, while the corresponding (S)-enantiomer had a potent and selective serotonin 5-HT3 receptor binding affinity.     

Cyclopropane-based stereochemical diversity-oriented conformational restriction strategy: histamine H3 and/or H4 receptor ligands with the 2,3-methanobutane backbone

The stereochemical diversity-oriented conformational restriction strategy can be an efficient method for developing specific ligands for drug target proteins. To develop potent histamine H(3) and/or H(4) receptor ligands, a series of conformationally restricted analogs of histamine with a chiral trans- or cis-4-amino-2,3-methano-1-(1H-imidazol-4-yl)butane structure was designed based on this strategy. These stereochemically diverse compounds were synthesized from previously developed versatile chiral cyclopropane units. Among these analogs, a trans-cyclopropane-type compound, (2S,3R)-4-(4-chlorobenzylamino)-2,3-methano-1-(1H-imidazol-4-yl)butane (5b), has remarkable antagonistic activity to both the H(3) (K(i) = 4.4 nM) and H(4) (K(i) = 5.5 nM) receptors, and a cis-cyclopropane-type compound, (2R,3R)-4-amino-2,3-methano-1-(1H-imidazol-4-yl)butane (6a), is a potent and selective H(3) receptor partial agonist (K(i) = 5.4 nM). Although (2S,3R)-4-amino-2,3-methano-1-(1H-imidazol-4-yl)butane (5a) does not have a hydrophobic group which the usual H(3) receptor antagonists have, it was found to be a potent H(3) receptor antagonist (K(i) = 20.1 nM). Thus, a variety of compounds with different pharmacological properties depending on the cyclopropane backbones and also on the side-chain functional groups were identified. In addition to the previously used 1,2-methanobutane backbone, the 2,3-methanobutane backbone also worked effectively as a cyclopropane-based conformational restriction structure. Therefore, the combination of these two cyclopropane backbones increases the stereochemical and three-dimensional diversity of compounds in this strategy, which can provide a variety of useful compounds with different pharmacological properties.     

Multigram-scale syntheses, stability, and photoreactions of A2A adenosine receptor antagonists with 8-styrylxanthine structure: potential drugs for Parkinson's disease

The improved multigram-scale syntheses of the important 8-styrylxanthine A(2A) adenosine receptor antagonist MSX-2 (8), its water-soluble prodrug MXS-3 (9), and KW-6002 (16) are described. N-Alkylation reactions at different positions of uracil derivatives were optimized. Two different methods for xanthine formation from 6-amino-5-cinnamoylaminouracil precursors were investigated, (a) the elimination of water by alkaline catalysis and (b) hexamethyldisilazane as a condensing agent; the latter was found to be superior. The photosensitivity of 8-styrylxanthines was studied. The (E)-configurated stryrylxanthine MSX-2 (8) isomerized in diluted solution, and the resulting (Z)-isomer (10a) was isolated and characterized. Furthermore, we describe for the first time that solid 8-styrylxanthines can dimerize upon exposition to daylight or irradiation with UV light. The resulting cyclobutane derivatives with head-to-tail (syn) configuration exhibited a considerably lower A(2A) adenosine receptor affinity than their parent compounds. The dimerization product of MSX-2 was a moderately potent nonselective A(1) and A(2A) antagonist (K(i)(A(1)) = 273 nM, K(i) (A(2A)) = 175 nM) while the dimer of the related compound KW-6002 was inactive at A(1) and only weakly active at A(2A) adenosine receptors (K(i) = 1.57 microM). The light sensitivity of 8-styrylxanthine derivatives, not only in solution, but also in the solid state, has to be considered when using those compounds as pharmacological tools or drugs.     

Exploitation of an additional hydrophobic pocket of σ1 receptors: late-stage diverse modifications of spirocyclic thiophenes by C-H bond functionalization

The hypothesis that the σ(1) receptor will tolerate an additional aryl moiety in position 1 of the spirocyclic system was based on spirocyclic pyrazole derivatives, pharmacophore models of σ(1) receptor ligands and DFT calculations. The strategy of introducing the aryl residue at the final step of the synthesis allowed the preparation of a large set of diverse ligands for the exploitation of the hydrophobic pocket of the σ(1) receptor protein. The catalyst system PdCl(2)/2,2'-bipyridyl/Ag(2)CO(3) is able to introduce various aryl groups onto the α-positions of spirocyclic thiophene derivatives 5 and 6 to afford the target aryl-appended spirocyclic thiophenes 3 and 4. Although the σ(1) affinity of the 1-phenyl substituted spirocyclic thiophenes 3a and 4a is slightly reduced compared with the σ(1) affinity of the non-arylated compounds 5 and 6, both compounds represent very potent σ(1) receptor ligands (3a: K(i) = 4.5 nM; 4a: K(i) = 1.0 nM). This result indicates that an aryl moiety in position 1 is well tolerated by the σ(1) receptor protein. The substitution pattern of the additional phenyl moiety has only weak effects on the σ(1) affinity. Even ligands 3f and 4h with extended naphthyl residue show high σ(1) affinity. However, decrease of σ(1) affinity by extension of the π-system to a biphenylyl substituent (4j: K(i) = 30 nM) indicates that the biphenylyl residue is too large for the primary hydrophobic binding pocket of the σ(1) receptor.     

New pyrazolo[3,4-b]pyridones as selective A(1) adenosine receptor antagonists: synthesis, biological evaluation and molecular modelling studies

A series of ethyl 4-amino-1-(2-chloro-2-phenylethyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylates () has been synthesized as potential A(1) adenosine receptor (A(1) AR) ligands. Binding affinities of the new compounds were determined for adenosine A(1), A(2A) and A(3) receptors. Compounds and showed good affinity (K(i)= 299 nM and 517 nM, respectively) and selectivity towards A(1) AR, whereas showed good affinity for A(2A) AR (K(i)= 290 nM), higher than towards A(1) AR (K(i)= 1000 nM). The only arylamino derivative of the series displayed high affinity (K(i)= 4.6 nM) and selectivity for A(3) AR. Molecular modelling and 3D-QSAR (CoMFA) studies carried out on the most active compounds gave further support to the pharmacological results.     

Automated parallel solid-phase synthesis of non-peptide CCR1 receptor antagonists

An automated, parallel, solid-phase synthesis and screening strategy using commercially available aryl acetic acids as starting materials has discovered novel, non-peptide CCR1 antagonists (K(i) < 100 nM).     

Ligand-based combinatorial design of selective purinergic receptor (A2A) antagonists using self-organizing maps

A virtual screening procedure based on a topological pharmacophore similarity metric and self-organizing maps (SOM) was developed and applied to optimizing combinatorial products functioning as P(1) purinergic receptor antagonists. The target was the human A(2A) receptor. A SOM was developed using a set of biologically tested molecules to establish a preliminary structure-activity relationship. A combinatorial library design was performed by projecting virtually assembled new molecules onto the SOM. A small focused library of 17 selected combinatorial products was synthesized and tested. On average, the designed structures yielded a 3-fold smaller binding constant ( approximately 33 vs approximately 100 nM) and 3.5-fold higher selectivity (50 vs 14) than the initial library. The most selective compound obtained revealed a 121-fold relative selectivity for A(2A) with K(i) (A(2A)) = 2.4 nM, and K(i) (A(1)) = 292 nM. This result demonstrates that it was possible to design a small, activity-enriched focused library with an improved property profile using the SOM virtual screening approach. The strategy might be particularly useful in projects in which structure-based design cannot be applied because of a lack of receptor structure information, for example, in the many projects aiming at finding new GPCR modulators.     

A new class of arylpiperazine derivatives: the library synthesis on SynPhase lanterns and biological evaluation on serotonin 5-HT(1A) and 5-HT(2A) receptors

An efficient solid-supported method for the synthesis of a new class of arylpiperazine derivatives containing amino acid residues has been developed. A 72-membered library was synthesized on SynPhase Lanterns functionalized by a BAL linker. A one-pot cleavage/cyclization step of aspartic and glutamic acid derivatives yielded succinimide- and pyroglutamyl-containing ligands (chemsets 9 and 10). The library representatives under study showed different levels of affinity for 5-HT(1A) and 5-HT(2A) receptors (estimated K(i) = 24-4000 and 1-2130 nM, respectively). Several dual 5-HT(1A)/5-HT(2A) ligands were found, of which two (9(3,3) and 9(3,5)) displayed high 5-HT(2A) affinity comparable to that of the reference drug ritanserin. A set of individual fragment contributions for the prediction of 5-HT(1A) and 5-HT(2A) affinity of all the library members were defined on the basis of the Free-Wilson analysis of 26 compounds. An alkylarylpiperazine fragment had essentially the same impact on the affinity for both receptors, whereas different terminal amide fragments were preferred by 5-HT(1A) (chemset 17, R(2) = adamantyl) and 5-HT(2A) (chemset 9, R(2) = norborn-2-ylmethyl) binding sites.     

Utility of Arylamido Ligands in Yttrium and Lanthanide Chemistry(1)

The reactivity of KNHAr reagents (Ar = C(6)H(5), C(6)H(3)Me(2)-2,6, C(6)H(3)(i)Pr(2)-2,6) with lanthanide and yttrium trichlorides has been investigated. With the larger metals Nd and Sm and the smaller 2,6-dimethyl-substituted ligand, the bimetallic dianionic complexes [K(THF)(6)](2)[Ln(&mgr;-NHC(6)H(3)Me(2)-2,6)(NHC(6)H(3)Me(2)-2,6)(3)](2) (Ln: Sm, 1a; Nd, 1b) are isolated as the potassium salts. Under the same reaction conditions YCl(3) forms a bimetallic anion which retains chloride: [K(DME)(2)(THF)(3)][Y(2)(&mgr;-NHC(6)H(3)Me(2)-2,6)(2)(&mgr;-Cl)(NHC(6)H(3)Me(2)-2,6)(4)(THF)(2)], 2. With the larger 2,6-diisopropyl ligands, neutral complexes are isolated in both solvated monometallic and unsolvated bimetallic forms. With Nd, a distorted octahedral trisolvate, Nd(NHC(6)H(3)(i)Pr(2)-2,6)(3)(THF)(3), 3, was obtained, whereas with Yb and Y the trigonal bipyramidal disolvates, Ln(NHC(6)H(3)(i)Pr(2)-2,6)(3)(THF)(2) (Ln: Yb, 4a; Y, 4b), were isolated. THF-free complexes of the NHC(6)H(3)(i)Pr(2)-2,6 ligand are available by reacting the amine NH(2)C(6)H(3)(i)Pr(2)-2,6 with Ln[N(SiMe(3))(2)](3) complexes. By this route, the dimers [Ln(&mgr;-NHC(6)H(3)(i)Pr(2)-2,6)(NHC(6)H(3)(i)Pr(2)-2,6)(2)](2) (Ln: Yb, 5a; Y, 5b) were isolated. The reaction of the unsubstituted arylamido salt KNHC(6)H(5) with NdCl(3) produced an insoluble material which was characterized as [Nd(NHC(6)H(5))(3)(KCl)(3)], 6. 6 reacted with Al(2)Me(6) in hexanes and produced a heteroleptic mixed-metal complex {[Me(2)Al(&mgr;-Me(2))](2)Nd(&mgr;(3)-NC(6)H(5))(&mgr;-Me)AlMe}(2), 7, and the trimeric aluminum arylamido complex [Me(2)Al(&mgr;-NHC(6)H(5))](3), 8. The solvent of crystallization and relevant crystallographic data for the compounds identified by X-ray analysis follow: 1a,THF, 156 K, P2(1)/n, a = 12.985(2) ?, b = 27.122(5) ?, c = 17.935(3) ?, beta = 100.19(1) degrees, V = 6216(1) ?(3), Z = 2, 6148 reflections (I > 3sigma(I)), R(F)() = 7.1%; 1b,THF, 156 K, P2(1)/n, a = 12.998(2) ?, b = 27.058(3) ?, c = 17.962(2) ?, beta = 99.74(1) degrees, V = 6225(1) ?(3), Z = 2; 2,DME/hexanes, P2(1)/n, a = 23.335(2) ?, b = 12.649(1) ?, c = 27.175(3) ?, beta = 96.36(1) degrees, V = 7971(1) ?(3), Z = 4, 2788 reflections (I > 3sigma(I)), R(F)() = 9.5%; 3, THF, P2(1), a = 12.898(1) ?, b = 16.945(1) ?, c = 13.290(1) ?, beta = 118.64(2) degrees, V = 2549.3(3) ?(3), Z = 2, 3414 reflections (I > 3sigma(I)), R(F)() = 4.3%; 4a, hexanes, P2(1), a = 9.718(2) ?, b = 19.119(3) ?, c = 12.640(2) ?, beta = 112.08(1) degrees, V = 2176.3(6) ?(3), Z = 2, 2933 reflections (I > 3sigma(I)), R(F)() = 4.3%; 4b, hexanes, 158 K, a = 9.729(2) ?, b = 19.095(5) ?, c = 12.744(1) ?, beta = 112.11(1) degrees, V = 2193.4(6) ?(3); 5b, hot toluene, 158 K, P2(1), a =19.218(9) ?, b = 9.375(3) ?, c = 19.820(5) ?, beta = 110.25(2) degrees, V = 3350(2)?(3), Z = 2, 1718 reflections (I > 2sigma (I)), R1 = 9.7%; 7, hexanes, 156 K, P&onemacr;, a = 9.618(3) ?, b = 12.738(4) ?, c = 9.608(3) ?, alpha = 99.32(1) degrees, beta = 108.87(1) degrees, gamma = 94.23(1) degrees, V = 1089.1(6) ?(3), Z = 2, 2976 reflections (I > 3sigma(I)), R(F)() = 3.9%; 8, hexanes, 156 K, Pcab, a = 23.510(5) ?, b = 25.462(5) ?, c = 8.668(2) ?, V = 5188(1) ?(3), Z = 8, 1386 reflections (I > 3sigma(I)), R(F)() = 5.7%.     

Synthesis, NMR conformational analysis and pharmacological evaluation of 7,7a,13,14-tetrahydro-6H-cyclobuta[b]pyrimido[1,2-a:3,4-a']diindole analogues as melatonin receptor ligands

A structure for the self-condensation product of 2-(1H-indol-2-yl)ethyl tosylate 2a, previously proposed as 6,7,14,15-tetrahydro-15aH-azocino[1,2-a:6,5-b]diindole 3a, was revised based on the (13)C-2D-INADEQUATE experiment, and proved to be 7,7a,13,14-tetrahydro-6H-cyclobuta[b]pyrimido[1,2-a:3,4-a']diindole 4a. A mechanism for the unexpected formation of this novel hexacyclic heterocycle was proposed and its NMR solution structure was elucidated. Five derivatives of the title ring skeleton 12-16 designed as melatonin receptor ligands were synthesized and their affinities for the human MT(1) and MT(2) receptors were determined. Both butyramides 13 and 15, as well as the non-methoxy acetamide 12 exhibited micromolar binding affinities for both receptors being slightly MT(2) selective. The methoxy acetamide 14 showed the best pharmacological profile exhibiting a five times higher affinity for MT(1) (K(i) = 49 nM) than for MT(2) (K(i) = 246 nM) receptor.     

Benzimidazole derivatives. 4. The recognition of the voluminous substituent attached to the basic amino group of 5-HT4 receptor antagonists

We report a structure-affinity analysis of an important element in the pharmacophore model for the recognition of 5-HT4 receptor antagonists: the voluminous substituent attached to the basic nitrogen of the ligand. We have designed, synthesized and pharmacologically evaluated a series of benzimidazole derivatives 1 containing a common molecular skeleton formed by N-[(4-piperidyl)methyl]-6-chlorobenzimidazole-4-carboxamide and four different substituents (R = butyl, 2-[(methylsulfonyl)amino]ethyl, 5-[(phenylacetyl)amino]pentyl, and 5-[(benzylsulfonyl)amino]pentyl). These compounds possess binding affinities in the nM range (Ki = 0.11-1.50 nM). Moreover, a ligand that contains a hydrogen atom attached to the basic nitrogen (R = H; Ki = 150 nM) is used as a control for structure-affinity relationships.     

Synthesis and serotonin 2 (5-HT2) receptor antagonist activity of 5-aminoalkyl-substituted pyrrolo[3,2-c]azepines and related compounds

A series of 5-aminoalkylpyrrolo[3,2-c]azepine derivatives was synthesized and their serotonin 2 (5-HT2) receptor antagonist and antiplatelet aggregation activities were evaluated. 5-HT2 receptor antagonist activity was largely determined by the nature of the substituent at the 8-position as well as the aminoalkyl group at the 5-position of the pyrrolo[3,2-c]azepine ring. Compound 18a, 5-[3-[4-(4-fluorophenyl)piperazin-1-yl]propyl]-8-hydroxy-1-methyl- 1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepin-4-one, was recognized as having potent 5-HT2 receptor antagonist activity with weak alpha1 adrenoceptor blocking activity and no significant D2 receptor binding affinity, while the corresponding isomeric pyrrolo[3,4-c]azepine derivative (22) displayed only weak 5-HT2 receptor antagonist activity. After racemic 18a was resolved directly via diastereomeric salt formation, each enantiomer was evaluated precisely. The 5-HT2 receptor antagonist activity of 18a was found to reside primarily in (-)-18a (which was about 14-fold more potent than (+)-18a in isolated guinea pig arteries). Consequently, (S)-(-)-18a (SUN C5174) displayed the overall best profile with potent 5-HT2 receptor antagonist activity (pA2=8.98+/-0.06) and high selectivity versus other receptors. SUN C5174 showed a marked inhibitory effect on the platelet aggregation induced by serotonin in combination with collagen and adenosine diphosphate (ADP) in canine or human platelet-rich plasma (IC50=6.5 to 16 nM). Moreover, this compound significantly inhibited the mortality rate in mouse acute pulmonary thromboembolytic death induced by collagen and serotonin at oral doses of 0.3 mg/kg or higher. SUN C5174 is currently undergoing clinical evaluation.     

Molecular interactions of new pregnenedione derivatives

The in vitro inhibitory activity of five new progesterone derivatives: 17alpha-hydroxy-16beta-methylpregna-1,4,6-triene-3,20-dione 1; 16beta-methyl-17alpha-toluoyloxypregna-1,4,6-triene-3,20-dione 2; 17alpha-hydroxy-6-methylenepregn-4-ene-3,20-dione 3; 6-methylene-17alpha-toluoyloxypregn-4ene-3,20-dione 4 and 17alpha-(p-bromobenzoyloxy)-6-methylenepregn-4-ene-3,20-dione 5 was determined. These compounds were evaluated as 5alpha-reductase inhibitors as well as antagonists for the androgen receptor. Compounds 1, 2, 3, 4 and 5 showed the following inhibitory activity for the 5alpha-reductase enzyme with IC(50) values of: 1 (1.65 microM), 2 (10 microM), 3 (19 nM), 4 (100 nM) and 5 (100 nM). The results of this study also showed the effect of increasing concentrations of the novel steroids upon [(3)H]dihydrotestosterone binding to androgen receptors from male hamster prostate. The K(i) values for compounds 1, 2, 3, 4, 5 and dihydrotestosterone showed the following order of affinity for the androgen receptor: 4>5>dihydrotestosterone>2>3>1. The overall data indicated that all synthesized compounds 1, 2, 3, 4 and 5 are inhibitors of the 5alpha-reductase enzyme present in the hamster prostate. In addition compounds 1, 2, 3, 4 and 5 also presented an affinity for the androgen receptor.     

二价铥三元碘化物研究

用一步法合成了ATmI₃(A=K,Rb,Cs)和A₄TmI₆(A=Rb,Cs)两类化合物.用X射线粉末衍射法确定其晶体结构.CsTmI₃、RbTmI₃和KTmI₃都属正交晶系,Z=4.CsTmI₃:a=0.8689(3)nm,b=1.2339(4)nm,c=0.8565(3)nm,空间群Pnma;RbTmI₃:a=1.0381(3)nm,b=0.4686(3)nm,c=1.7256(9)nm,空间群Pnma;KTmI₃:a=0.4576(2)nm,b=1.5133(20)nm,c=1.1679(6)nm,空间群Pmcm;3种结构中八面体结构单元[TmI₆]的连接方式不同,分别为共顶点、共棱和共顶点同时共棱方式连接.Cs、Rb和K原子的配位数依次下降,分别为10、9和8.Cs₄TmI₆和Rb₄TmI₆的结构属于K₄CdCl₆型,三方晶系,空间群R3 c,Z=6.Cs₄TmI₆:a=1.4516(1)nm,C=1.8292(2)nm,Rb₄TmI₆:a=1.41714(9)nm,c=1.7473(1)nm.     

t-Bu2SiF-derivatized D2-receptor ligands: the first SiFA-containing small molecule radiotracers for target-specific PET-imaging

The synthesis, radiolabeling and in vitro evaluation of new silicon-fluoride acceptor (SiFA) derivatized D(2)-receptor ligands is reported. The SiFA-technology simplifies the introduction of fluorine-18 into target specific biomolecules for Positron-Emission-Tomography (PET). However, one of the remaining challenges, especially for small molecules such as receptor-ligands, is the bulkiness of the SiFA-moiety. We therefore synthesized four Fallypride SiFA-conjugates derivatized either directly at the benzoic acid ring system (SiFA-DMFP, SiFA-FP, SiFA-DDMFP) or at the butyl-side chain (SiFA-M-FP) and tested their receptor affinities. We found D(2)-receptor affinities for all compounds in the nanomolar range (K(i(SiFA-DMFP)) = 13.6 nM, K(i(SiFA-FP)) = 33.0 nM, K(i(SiFA-DDMFP)) = 62.7 nM and K(i(SiFA-M-FP)) = 4.21 nM). The radiofluorination showed highest yields when 10 nmol of the precursors were reacted with [(18)F]fluoride/TBAHCO(3) in acetonitrile. After a reversed phased cartridge purification the desired products could be isolated as an injectable solution after only 10 min synthesis time with radiochemical yields (RCY) of more than 40% in the case of SiFA-DMFP resulting in specific activities >41 GBq/μmol (>1,100 Ci/mmol). Furthermore, the radiolabeled products were shown to be stable in the injectable solutions, as well as in human plasma, for at least 90 min.     

New serotonin 5-HT(6) ligands from common feature pharmacophore hypotheses

Serotonin 5-HT6 receptor antagonists are thought to play an important role in the treatment of psychiatry, Alzheimer's disease, and probably obesity. To find novel and potent 5-HT6 antagonists and to provide a new idea for drug design, we used a ligand-based pharmacophore to perform the virtual screening of a commercially available database. A three-dimensional common feature pharmacophore model was developed by using the HipHop program provided in Catalyst software and was used as a query for screening the database. A recursive partitioning (RP) model which can separate active and inactive compounds was used as a filtering system. Finally a sequential virtual screening procedure (SQSP) was conducted, wherein both the common feature pharmacophore and the RP model were used in succession to improve the results. Some of the hits were selected based on druglikeness, ADME properties, structural diversity, and synthetic accessibility for real biological evaluation. The best hit compound showed a significant IC50 value of 9.6 nM and can be used as a lead for further drug development.     

Synthesis and characterization of Mo(6) chalcobromides and cyano-substituted compounds built from a novel [(Mo(6)Br(i)(6)Y(i)(2))L(a)(6)](n)()(-) discrete cluster unit (Y(i) = S or Se and L(a) = Br or CN)

The syntheses, crystal structures determined by single-crystal X-ray diffraction, and characterizations of new Mo(6) cluster chalcobromides and cyano-substituted compounds with 24 valence electrons per Mo(6) cluster (VEC = 24), are presented in this work. The structures of Cs(4)Mo(6)Br(12)S(2) and Cs(4)Mo(6)Br(12)Se(2) prepared by solid state routes are based on the novel [(Mo(6)Br(i)(6)Y(i)(2))Br(a)(6)](4)(-) (Y = S, Se) discrete units in which two chalcogen and six bromine ligands randomly occupy the inner positions, while the six apical ones are fully occupied by bromine atoms. The interaction of these two compounds with aqueous KCN solution results in apical ligand exchange giving the two first Mo(6) cyano-chalcohalides: Cs(0.4)K(0.6)(Et(4)N)(11)[(Mo(6)Br(6)S(2))(CN)(6)](3).16H(2)O and Cs(0.4)K(0.6)(Et(4)N)(11)[(Mo(6)Br(6)Se(2))(CN)(6)](3).16H(2)O. Their crystal structures, built from the original [(Mo(6)Br(i)(6)Y(i)(2))(CN)(a)(6)](4)(-) discrete units, will be compared to those of the two solid state precursors and other previously reported Mo(6) cluster compounds. Their redox properties and (77)Se NMR characterizations will be presented. Crystal data: Cs(4)Mo(6)Br(12)S(2), orthorhombic, Pbca (No. 61), a = 11.511(5) A, b = 18.772(5) A, c = 28.381 A (5), Z = 8; Cs(4)Mo(6)Br(12)Se(2), Pbca (No. 61), a = 11.6237(1) A, b = 18.9447(1) A, c = 28.4874(1) A, Z = 8; Cs(0.4)K(0.6)(Et(4)N)(11)[(Mo(6)Br(6)S(2))(CN)(6)](3).16H(2)O, Pm-3m (No. 221), a = 17.1969(4) A, Z = 1; Cs(0.4)K(0.6)(Et(4)N)(11)[(Mo(6)Br(6)Se(2))(CN)(6)](3).16H(2)O, Pm-3m (No. 221), a = 17.235(5) A, Z = 1.     

Synthesis of novel apio carbocyclic nucleoside analogues as selective a(3) adenosine receptor agonists

On the basis of the biological activity of neplanocin A and apio-dideoxyadenosine (apio-ddA), novel apio-neplanocin A analogues 5a-d, combining the properties of two nucleosides, were stereoselectively synthesized. The apio moiety of the target nucleosides 5a-d was stereoselectively introduced by treating lactol 10 with 37% formaldehyde in the presence of potassium carbonate. The carbasugar moiety of neplanocin A was successively built by exposing diene 12 on a Grubbs catalyst in methylene chloride. The final nucleosides 5a-d were synthesized from the condensation of the glycosyl donor 14 with nucleic bases under the standard Mitsunobu conditions. Similarly, apio-aristeromycin 6 and (N)-apio-methanocarbaadenosine 7 were derived from the common intermediate 13 using catalytic hydrogenation and Simmons-Smith cyclopropanation as key steps. All of the final nucleosides 5a-d, 6, and 7 did not show significant inhibitory activity against S-adenosylhomocysteine hydrolase (SAH) up to 100 muM, maybe due to the absence of the secondary hydroxyl group at the C3'-position, which should be oxidized by cofactor-bound NAD(+). However, apio-neplanocin A (5a) showed potent and highly selective binding affinity (K(i) = 628 +/- 69 nM) at the A(3) adenosine receptor without any binding affinity at the A(1) and A(2A) adenosine receptors. In conclusion, we have first developed novel carbocyclic nucleosides with unnatural apio-carbasugars using stereoselective hydroxymethylation and RCM reaction and also discovered a new template of human A(3) adenosine receptor agonist, which play a great role in developing new A(3) adenosine receptor agonist as well as in identifying the binding site of the receptor.     

Synthesis, 5-hydroxytryptamine1A receptor affinity and docking studies of 3-[3-(4-aryl-1-piperazinyl)-propyl]-1H-indole derivatives

A series of 3-[3-(4-aryl-1-piperazinyl)-propyl]-1H-indole derivatives (12a-h) was synthesized and evaluated for binding affinity at the human 5-hydroxytryptamine(1A) receptor (5-HT(1A)R) compounds (12b) and (12h) showed the highest 5-HT(1A) receptor affinity (IC(50)=15 nM). Molecular docking studies with all the compounds in a homology model of 5-HT(1A) showed that the main interaction anchoring the ligand in the receptor was a charge-reinforced bond between the protonated nitrogen atom (N-4) of the piperazine ring and Aspartate(3.32).