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J L Mokrosz

Publications and source records attributed to J L Mokrosz.

At least 19 recordsLinked to original sources
PubMed1996

8-[4-[2-(1,2,3,4-Tetrahydroisoquinolinyl]butyl-8-azaspiro[4.5]decane-7,9-dione: a new 5-HT1A receptor ligand with the same activity profile as buspirone.

A new analog of buspirone (1), i.e., 8-[4-[2-(1,2,3,4-tetrahydroisoquinolinyl)]butyl]-8-azaspiro- [4.5]decane-7,9-dione (6a), was synthesized. In was demonstrated that buspirone and its analog 6a were equipotent 5-HT(1A) ligands. Several behavioral models showed that 6a had essentially the same functional profile at 5-HT(1A) receptors as buspirone. The obtained results permit a conclusion that the basic nitrogen atom and terminal, bulky cycloimide moiety, but not the 2-pyrimidinyl group, of buspirone are directly involved in the formation of the bioactive complex with 5-Ht1A receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1996

3-(omega-Aminoalkyl)-5,5-dialkyl(or spirocycloalkyl-1',5-)hydantoins as new 5-HT1A and 5-HT2A receptor ligands.

A series of new 3-(omega-aminoalkyl)-5,5-disubstituted hydantoins, containing 1-phenylpiperazine, 1-(o-methoxyphenyl)piperazine or 1,2,3,4-tetrahydroisoquinoline fragments, were synthesized by standard alkylation procedures and their 5-HT1A and 5-HT2A receptor affinities were determined. It has been shown that the investigated derivatives are recognized by 5-HT1A and 5-HT2A receptors due to the presence of a 1-arylpiperazine fragment however, the terminal hydantoin moiety plays an important role in stabilization of the receptor-ligand complex. It has also been found that the two 1-phenylpiperazine derivatives 32 and 36 are new selective 5-HT2A receptor ligands (Ki = 34 and 37 nM, respectively), whereas the derivative of 1-(o-methoxyphenyl)piperazine (38) is a new, highly potent 5-HT1A receptor ligand (Ki = 0.51 nM) with a moderate affinity for 5-HT2A receptors (Ki = 213 nM).

Amines↗
PubMed1996

Structure-activity relationship studies of CNS agents, Part 31: Analogs of MP 3022 with a different number of nitrogen atoms in the heteroaromatic fragment--new 5-HT1A receptor ligands.

Two series of new MP 3022 analogs, i.e. 1-(o-methoxyphenyl)-4-n-propylpiperazines (3, 4a, 4b, 6-9, and 12-13) and 2-(n-propyl)-1,2,3,4-tetrahydroisoquinolines (5a, 5b, 11a, and 11b) containing a terminal heteroaromatic system with a different number of nitrogen atoms, were synthesized and their 5-HT1A/5-HT2A and alpha 1 receptor affinity was assayed. The majority of investigated piperazines may be classified as non-selective 5-HT1A/5-HT2A/alpha 1 receptor ligands. Compounds 3, 4a, 4b, 7-9a with the highest affinity for 5-HT1A receptors (Ki = 4-54 nM) were tested in vivo. Their functional activity was differentiated; while 3, 8, and 9a behaved like weak antagonists of postsynaptic 5-HT1A receptors, 4b and 7 may be classified as potential partial 5-HT1A receptors, agonists. Isomer 4a has characteristic features of a potential weak postsynaptic 5-HT1A receptor agonist.

Animals↗
PubMed1996

Structure-activity relationship studies of CNS agents. Part 24: New analogs of N-tert.-butyl-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-phenylpropanamide (WAY-100135).

A series of new N-substituted derivatives of 3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-phenylpropanamide, 6-10, were synthesized and their 5-HT1A, 5-HT2A, and alpha 1 receptor affinities were determined. All the compounds were highly potent 5-HT1A ligands with a moderate or low 5-HT2A and alpha 1 affinity. It was shown that the 5-HT2A affinity of 1 and 6-10 depended crucially on the volume of amide substituents. None of the investigated racemic mixtures 1 and 6-8 antagonized the 8-OH-DPAT-induced lower lip retraction in rats, whereas (+/-)-7 behaved like a weak agonist of 5-HT1A receptors in the model used.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1995

Structure-activity relationship studies of CNS agents, XIX: Quantitative analysis of the alkyl chain effects on the 5-HT1A and 5-HT2 receptor affinities of 4-alkyl-1-arylpiperazines and their analogs.

The 5-HT1A and 5-HT2 receptor affinity of a set of 44 N-alkylated 1-aryl-piperazines and their analogs has been analyzed: the n-hexyl derivatives were the most potent and the most selective 5-HT1A ligands of all the investigated N-alkyl homologues. The alkyl chain may stabilize the 5-HT1A receptor-ligand complex by hydrophobic forces. A set of the alkyl substituent contributions (CHT1A) for prediction of the 5-HT1A affinity of N-alkyl derivatives of 1-arylpiperazines and related compounds have been defined on the basis of the Free-Wilson analysis.

Animals↗
PubMed1995

Structure-activity relationship studies of CNS agents--XVII. Spiro[piperidine-4',1-(1,2,3,4-tetrahydro-beta-carboline)] as a probe defining the extended topographic model of 5-HT1A receptors.

Spiro[piperidine-4',1-(1,2,3,4-tetrahydro-beta-carboline)] (10), its derivatives 11-15 and its analogs 16 and 17 were examined as ligands of serotonin 5-HT1A receptors. It was shown that compounds 12 and 14 had essentially the same 5-HT1A affinity as 1-phenylpiperazine and its rigid analog 7, whereas there were substantial differences in the steric arrangement of their crucial pharmacophores, i.e. aromatic and protonation centers. On the basis of the existing models and using the (+)-LSD structure as a template, a new, extended three-point topographic model of 5-HT1A receptors has been proposed.

Animals↗
PubMed1994

Structure-activity relationship studies of central nervous system agents. 13. 4-[3-(Benzotriazol-1-yl)propyl]-1-(2-methoxyphenyl)piperazine, a new putative 5-HT1A receptor antagonist, and its analogs.

A new set of 4-alkyl-1-(o-methoxyphenyl)piperazines containing a terminal benzotriazole fragment were synthesized, and their 5-HT1A and 5-HT2 affinity was determined. It was shown that the benzotriazole moiety contributes to both the 5-HT1A and 5-HT2 receptor affinity. It was demonstrated in several behavioral models that 4-[3-(benzotriazol-1- yl)propyl]-1-(2-methoxyphenyl)piperazine (11) is a new, potent presynaptic and postsynaptic 5-HT1A receptor antagonist. However, it is not selective for 5-HT1A versus alpha 1 receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1994

Structure-activity relationship studies of CNS agents. XII. 1-[4-(4-aryl-1-piperazinyl)butyl]-3,4-dihydro-2(1H)-quinolinones: new 5-HT1A, 5-HT2 and D2 ligands with a potential antipsychotic activity.

The synthesis of three 1-[4-(4-aryl-1-piperazinyl)butyl]-3,4-dihydro-2(1H)-quinolinones (5-7) was described and the receptor binding profile (5-HT1A, 5-HT2, alpha 1, D1, D2) was determined. It was found that m-chloro (5) and o-methoxy (6) derivatives are potent antagonists of the 5-HT1A, 5-HT2 and D2 receptors. It was shown that compound 6 resembles very well some atypical antipsychotics and may be considered as a novel agent of this class of drugs.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1994

Structure-activity relationship studies of CNS agents. Part 14: Structural requirements for the 5-HT1A and 5-HT2A receptor selectivity of simple 1-(2-pyrimidinyl)piperazine derivatives.

The 5-HT1A and 5-HT2A receptor affinity of model 1-(2-pyrimidinyl)-piperazine derivatives 15-21 and 23-32 has been determined. 2-(N-Methylpiperazino)-4,6-di(2-thienyl)pyrimidine 26 is a new, highly active and selective 5-HT2A receptor ligand. The topography of a molecule and the stereoelectronic effects of the thiophene rings are the major factors responsible for the high affinity and selectivity of 26 towards 5-HT2A sites.

Alkylation↗
PubMed1994

Structure-activity relationship studies of CNS agents. Part 10(1): 1-Aryl-2-[3-(4-aryl-1-piperazinyl)propyl]-1,4-dihydro-3(2H)-isoquino linones: two modes of the interaction with the 5-HT1A receptor site.

The synthesis and 5-HT1A and 5-HT2 receptor affinities of 1-aryl-2-[3-(4-aryl-1-piperazinyl)propyl]-1,4-dihydro-3(2H)- isoquinolinones 7-28 are reported. The two derivatives 7 and 13 were the most potent 5-HT1A ligands (Ki 1.72 +/- 0.07 and 2.75 +/- 0.59 nM, respectively) of all the investigated compounds. It has been found that the effect of the substituent in the 1-arylpiperazine portion is opposite to the observed in simple 1-arylpiperazine. The molecular modelling results indicate that the investigated derivatives may interact with 5-HT1A sites in two different ways: as ordinary 4-substituted 1-arylpiperazines, or in such a manner that the aryl substituent at position 1 of the 3(2H)-isoquinolinone moiety and N-4 piperazine atom mimics remarkably well the bioactive conformation of simple 1-arylpiperazines.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1993

Structure-activity relationship studies of CNS agents. Part 9: 5-HT1A and 5-HT2 receptor affinity of some 2- and 3-substituted 1,2,3,4-tetrahydro-beta-carbolines.

The 5-HT1A and 5-HT2 receptor affinity of 2- and 3-substituted 1,2,3,4-tetrahydro-beta-carbolines 1-8, 10 and 12-15 has been determined. It has been found that the specific 5-HT1A affinity of the protonated form (KiAH+) 2-n-hexyl derivatives 4, 8, 14 and (+)-LSD is of the same order. It has been shown by means of molecular modelling methods that pharmacophores of all the active compounds can adopt a common position at the 5-HT1A receptor model. The model also offers an explanation for the observed stereoselectivity chiral compounds.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1992

Stereoelectronic factors in the interaction with DNA of small aromatic molecules substituted with a short cationic chain: importance of the polarity of the aromatic system of the molecule.

We have performed a quantitative analysis of the interaction with DNA of several unfused aromatic compounds synthesized in our laboratory and substituted with one or two short cationic chains. These and similar literature compounds, for which DNA binding data are available, bind with DNA by partial intercalation of the aromatic system, groove interaction of the linker chain, and groove electrostatic interactions of the terminal cationic group. Several independent quantitative and qualitative approaches show consistently that the strength of the interaction of the aromatic unit of the molecule with DNA binding sites depends on the direction and magnitude of polarity of the aromatic system. The phenomenon is explained in terms of the greatest negative potential in the DNA grooves, a concept extensively elaborated by Pullman and Pullman [cf. Lavery, R. and Pullman, B. [(1985) J. Biomol. Struct. Dyn. 2, 1021-1032] and references therein]. Classical, fused-ring planar intercalators do not follow the polarity-DNA affinity correlation, presumably because the intercalative forces depend more strongly on polarizability than on polarity of the aromatic system.

Animals↗
PubMed1992

Structure-activity relationship studies of central nervous system agents. 5. Effect of the hydrocarbon chain on the affinity of 4-substituted 1-(3-chlorophenyl)piperazines for 5-HT1A receptor site.

The effect of the hydrocarbon chain of the model 4-substituted 1-(3-chlorophenyl)piperazines 12-31 on their affinity for 5-HT1A receptor sites was investigated. It was found that elongation of the 4-n-alkyl chain strongly increases the 5-HT1A affinity of the investigated compounds. The affinity reaches the maximum (Ki = 2.67 nM) for the n-hexyl derivative 20. It was shown that hydrophobic interactions of N-4 substituents of 1-arylpiperazines significantly contribute to their 5-HT1A affinity. The specific binding constant was defined as the receptor affinity of the protonated species of compounds under physiological conditions. The range of Ki(AH+) = 1 - 3 x 10(-11) M is a specific affinity limit of the investigated class of compounds at the 5-HT1A receptor sites.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1992

Structure-activity relationship studies of CNS agents. Part 4: 2-[3-(4-aryl-1-piperazinyl)propyl]-1,2,3,4-tetrahydro-beta-carbolin+ ++ -1-one derivatives as potential central anti-serotonin agents.

Seven derivatives of 1,2,3,4-tetrahydro-beta-carbolin-1-one have been prepared. Three of them showed significant central anti-serotonin activity, comparable with that of trazodone or etoperidone. Some structural features were found to be important for the central antiserotonin activity of the investigated class of compounds.

5-Hydroxytryptophan↗