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PubMed1990

Synthesis, biological evaluation, and quantitative structure-activity relationship analysis of [beta-(Aroylamino)ethyl]piperazines and -piperidines and [2-[(Arylamino)carbonyl]ethyl]piperazines, -pyrazinopyridoindoles, and -pyrazinoisoquinolines. A new class of potent H1 antagonists.

Some [beta-(Aroylamino)ethyl]piperazines and -piperidines and [2-[(Arylamino)carbonyl]ethyl]piperazines, -piperidines, -pyrazinopyridoindoles, and -pyrazinoisoquinolines have been synthesized and their H1-antagonistic activity studied in isolated guinea pig ileum. Quantitative structure-activity relationship analysis indicates that the hydrophobicity of the side chain of these compounds plays a major role in their activity while steric and electronic factors are of secondary importance. All these compounds act on a common receptor and appear to interact similarly with the receptor.

Amines↗

PubMed1978

Studies on 1-substituted 4-(1,2-diphenylethyl)piperazine derivatives and their analgesic activities. 2. Structure-activity relationships of 1-cycloalkyl-4-(1,2-diphenylethyl)piperazines.

Forty-six 1-cycloalkyl-4-(1,2-diphenylethyl)piperazines were synthesized. The influence of substituents on phenyl groups of 1-cycloalkyl-4-(1,2-diphenylethyl)piperazines 4a-c on the analgesic activity was investigated in experimental animals. The most active compounds, 5a-c, in this series had a m-hydroxyl group on the 2-phenyl group of 4a-c, while morphine has a phenolic hydroxyl group para to th- aminoethyl moiety. Their activities were 23-56 and 23-38 times those of their original compounds 4a-c and morphine, respectively, tested by the D'Amour-Smith method after subcutaneous administration.

Analgesics↗

PubMed1997

Synthesis and opiate activity of pseudo-tetrapeptides containing chiral piperazin-2-one and piperazine derivatives.

Enantiomeric piperazin-2-one derivatives, N,N'-ethylene-bridged alanylphenylalanines (1a or 1b), were synthesized using (S)- or (R)-alanine and phenylalanine as starting materials, and were inserted into the second and third positions of enantiomeric pseudo-tetrapeptides (P1a- or P1b-OEt). The corresponding piperazine derivatives (1a- or 1b-sRed) obtained by selective BH3 reduction of the amide carbonyl groups of 1a or 1b were similarly inserted into the same positions of tetrapeptides (P1a- and P1b-sRed). Enantiomeric N,N'-ethylene-bridged tyrosyltyrosine derivatives (2a or 2b) obtained from (S)- or (R)-tyrosine were also inserted into the first and second positions of two pairs of enantiomeric tetrapeptides (P2a- and P2b-OEt or P'2a- and P'2b-OEt). The opiate activities of the eight peptides thus obtained were studied by use of the mouse vas deferens and the guinea pig ilcum assays in order to elucidate the structure-activity relationships of these peptides, especially with respect to stereochemistry.

Alanine↗

PubMed1981

Possible mechanism of action of piperazine derivatives on liver mitochondria. I--Effect of p-toluyl m-nitro-piperazine (p-TNP).

The effect of p-toluyl m-nitro-piperazine on energy conservation processes in rat liver mitochondria is presented. The drug showed an inhibitory effect on the three segments of the respiratory chain and on the ATPase system. NADH oxidase and NADH dehydrogenase activity was inhibited 100%. The velocity and amplitude of swelling induced by glutamate, succinate, ascorbate + TMPD, and ATP was significantly changed by p-toluyl m-nitro-piperazine. It was suggested that the general action of the drug on mitochondrial metabolism would be concerning with modifications on mitochondrial membrane.

Adenosine Triphosphatases↗

PubMed2005

Piperazine-2,5-dione-oxalic acid-water (1/1/2) and a redetermination of piperazine-2,5-dione, both at 120 K: hydrogen-bonded sheets containing multiple ring types.

In piperazine-2,5-dione-oxalic acid-water (1/1/2), C4H6N2O2.C2H2O4.2H2O, both organic components lie across inversion centres in space group P-1. The molecules are linked by N-H...O and by both two-centre O-H...O and three-centre O-H...(O)2 hydrogen bonds into sheets built from R(1)(2)(5), R(2)(2)(8), R(4)(4)(8) and R(5)(4)(15) rings. In piperazine-2,5-dione, C4H6N2O2, where the molecules lie across centres of inversion in space group P2(1)/c, the molecules are linked by paired N-H...O hydrogen bonds into ribbons of centrosymmetric R(2)(2)(8) rings, which are further linked into sheets by C-H...O hydrogen bonds, generating R(4)(3)(14) rings between the ribbons.

Journal Article↗

PubMed1989

Preparation and biodistribution of 1-[2-(3-[125I]iodo-4-aminophenyl)ethyl]-4-[3-(trifluoromethyl) phenyl]piperazine and 1-[2-(3-[125I]iodo-4-azidophenyl)ethyl]-4-[3-(trifluoromethyl)phenyl] piperazine.

The iodinated analogue of 1-[2-(4-aminophenyl)ethyl]-4-[3-(trifluoromethyl)phenyl]piperazine (PAPP), IPAPP (4), and the corresponding azido compound azido-IPAPP (5) were synthesized. The corresponding no-carrier-added 125I (T1/2 = 60 days, 35-60 keV) labeled compounds were also prepared. High specific binding was observed from in vitro binding studies using rat brain tissue preparation; Ki = 20 and 17.5 nM against [3H]-5-HT. In vivo biodistribution studies in rats showed that azido-[125I]IPAPP passed through intact blood-brain barrier and localized in the brain. Ex vivo autoradiography of rat brain sections exhibited a diffuse uptake pattern, which may be due to specific and nonspecific binding. The results indicate that IPAPP and azido-IPAPP may not be suitable to image the serotonin receptor in the brain.

Animals↗

PubMed1998

Inhibitors of farnesyl protein transferase. 4-Amido, 4-carbamoyl, and 4-carboxamido derivatives of 1-(8-chloro-6,11-dihydro-5H-benzo[5,6]- cyclohepta[1,2-b]pyridin-11-yl)piperazine and 1-(3-bromo-8-chloro-6,11- dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)piperazine.

The synthesis of a variety of novel 4-amido, 4-carbamoyl and 4-carboxamido derivatives of 1-(8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl) piperazine to explore the SAR of this series of FPT inhibitors is described. This resulted in the synthesis of the 4- and 3-pyridylacetyl analogues 45a and 50a, respectively, both of which were orally active but were found to be rapidly metabolized in vivo. Identification of the principal metabolites led to the synthesis of a variety of new compounds that would be less readily metabolized, the most interesting of which were the 3- and 4-pyridylacetyl N-oxides 80a and 83a. Novel replacements for the pyridylacetyl moiety were also sought, and this resulted in the discovery of the 4-N-methyl and 4-N-carboxamidopiperidinylacetyl derivatives 135a and 160a, respectively. All of these derivatives exhibited greatly improved pharmacokinetics. The synthesis of the corresponding 3-bromo analogues resulted in the discovery of the 4-pyridylacetyl N-oxides 83b (+/-) and 85b [11S(-)] and the 4-carboxamidopiperidinylacetamido derivative 160b (+/-), all of which exhibited potent FPT inhibition in vitro. All three showed excellent oral bioavailability in vivo in nude mice and cynomolgus monkeys and exhibited excellent antitumor efficacy against a series of tumor cell lines when dosed orally in nude mice.

3T3 Cells↗

PubMed1989

Structure-activity relationships in a series of piperazine-2,3-dione containing penicillins and cephalosporins. II. Derivatives substituted at N(4) of the piperazine ring.

The structure-activity relationships within a series of penicillins and cephalosporins containing an N(4)-substituted piperazine-2,3-dione moiety in the C(6)/C(7)-beta-side chain are discussed.

Cephalosporins↗

PubMed1989

Synthesis and biological activity of a series of piperazine-2,3-dione containing penicillins and 6 alpha-formamidopenicillins. I. Derivatives substituted at C(5) or C(6) of the piperazine ring.

The synthesis and antibacterial activity of a series of penicillins and 6 alpha-formamidopenicillins containing a C(5) or C(6)-substituted piperazine-2,3-dione moiety in the C(6)-beta-sidechain is described.

Penicillins↗

PubMedDate not supplied

Piperazine derivatives of dimethylxanthines. IV. Reaction of beta,gamma-epoxypropyldimethylxanthines with piperazines.

In the reaction of 7-resp. 1-beta,gamma-epoxyproplderivatives of theophylline (Th) or theobromine (Tb) with piperazine and N-monoalkyl or monoarylpiperazines the corresponding 7-resp. 1-beta-hydroxy-gamma-piperazinopropyl-Th (1-8) resp. Tb (9-16) were formed. In preliminary screening some of the new compounds showed strong antagonism with histamine H1 receptor and with endogenous histamine.

Animals↗

PubMed1996

4-(2'-Methoxyphenyl)-1-[2'-[N-(2"-pyridinyl)-p-iodobenzamido]ethyl] piperazine and 4-(2'-methoxyphenyl)-1-[2'-[N-(2"-pyridinyl)-p- fluorobenzamido]ethyl]piperazine, two new antagonists at pre- and postsynaptic serotonin-1A receptors.

p-MPPI [4-(2'-methoxyphenyl)-1-[2'-[N-(2"-pyridinyl)-p-iodobenzamido] ethylpiperazine] and p-MPPF [4-(2'-methoxyphenyl)-1-[2'-[N-(2"-pyridinyl)-p- fluorobenzamido]ethyl]piperazine] competitively antagonized 5-HT1A receptor activation in the rat, as measured by hypothermia, forepaw treading and 5-HT turnover; they exhibited to partial agonist activity on any of these measures. When given i.p., p-MPPI and p-MPPF dose-dependently antagonized the hypothermia induced by 8-hydroxy-2- (di-n-propylamino)tetralin (8-OH-DPAT) (0.5 mg/kg), with approximate ID50 of 5 and 3 mg/kg, respectively. The inhibitory effect caused by a fixed dose of p-MPPI (6 mg/kg) or p-MPPF (3 mg/kg) was surmounted by higher doses of 8-OH-DPAT. p-MPPI and p-MPPF also attenuated the hypothermia induced by gepirone. Forepaw treading caused by 8-OH-DPAT (2 mg/kg) in reserpine-pretreated rats (1 mg/kg, s.c., 18-24 hr before the experiment) was dose-dependently antagonized by p-MPPI and p-MPPF with approximate ID50 of 3 and 0.7 mg/kg, respectively. p-MPPI also antagonized forepaw treading induced by 5-methoxy-N,N,-dimethyltryptamine (5-MeODMT) (5 mg/kg) and this antagonism was competitively overcome by higher doses of 5-methoxy-N,N,-dimethyltryptamine. p-MPPI and p-MPPF were able to antagonize the 8-OH-DPAT-(0.5 mg/kg) induced reduction in the 5-HIAA/5-HT ratio, a measure of 5-HT turnover in the hippocampus or striatum. No hypothermia or reciprocal forepaw treading was produced by either drug when given at doses as high as 10 mg/kg. Neither p-MPPI nor p-MPPF (10 mg/kg) given alone significantly altered the ratio of 5-HIAA/5-HT in the hippocampus or striatum. Also, binding of [3H]p-MPPF to hippocampal membranes was unaltered by the addition of 100 microM guanylyl-imidodiphosphate to the incubation medium. In conclusion, p-MPPI and p-MPPF behave, in vivo, as competitive antagonists of both postsynaptic 5-HT1A receptors and somatodendritic 5-HT1A autoreceptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2001

Comparative molecular field analysis of dopamine D4 receptor antagonists including 3-[4-(4-chlorophenyl)piperazin-1-ylmethyl]pyrazolo[1,5-a]pyridine (FAUC 113), 3-[4-(4-chlorophenyl)piperazin-1-ylmethyl]-1H-pyrrolo-[2,3-b]pyridine (L-745,870), and clozapine.

A CoMFA study was undertaken to elucidate the correlation of biological activity and structural parameters of 25 dopamine D4 antagonists. A special point of interest is that we have included the atypical D4 antagonist clozapine as a structural template for all other compounds. After comparing potential protonation sites at semiempirical (AM1) and ab initio (6-31G(d)) levels of theory, possible conformations of the lead compound 3-[4-(4-chlorophenyl)piperazin-1-ylmethyl]pyrazolo[1,5-a]pyridine (FAUC 113) were investigated by systematic semiempirical conformational analysis. The final conformation of FAUC 113, which was used as a template for the other compounds in the dataset, was chosen by clustering and rigid body alignment of all conformations to clozapine. The CoMFA applied on the final alignment resulted in a q2cv of 0.739. To elucidate the influence of the absolute orientation of the molecules within the grid space, the entire dataset was systematically rotated (1296 steps) within the lattice. The Gaussian-shaped distribution of the q2cv values spanned the range of 0.699-0.794 and therefore supports the significance of the analysis.

Clozapine↗

PubMed2004

3-[4-(4-fluorophenyl)piperazin-1-ylmethyl]-5-methyl-1,3-benzoxazol-2(3H)-one and 3-[4-(2-fluorophenyl)piperazin-1-ylmethyl]-5-methyl-1,3-benzoxazol-2(3H)-one.

The title compounds, both C(19)H(20)FN(3)O(2), contain essentially planar benzoxazolinone ring systems, within which the C-N bond distances and angles do not differ significantly between the two compounds. In both cases, the piperazine ring adopts an almost perfect chair conformation and the benzoxazolinone ring system lies nearly perpendicular to it. The structures contain intermolecular C-H.O contacts, and the interactions between the benzoxazolinone and fluorophenylpiperazine portions of the molecules are segregated.

Journal Article↗

PubMed1964