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M Froimowitz

Publications and source records attributed to M Froimowitz.

At least 37 records · Page 2Linked to original sources
PubMed1990

The development of computer simulations of the geometries and thermodynamics of biological molecules.

The historical development of computer simulations of molecular geometry and thermodynamics (molecular mechanics, force field method) is outlined. The advantages and disadvantages of techniques such as energy minimization, molecular dynamics and free energy perturbation are discussed. An example is included that shows how energy minimization studies of dopamine D-2 antagonists have been used to develop an understanding of the three-dimensional pharmacophore necessary for this pharmacological activity.

Computer Simulation↗
PubMed1990

Requirements for the activation of protein kinase C: comparison of the molecular geometries of phorbol and diacylglycerol.

MM2 calculations have been performed on a number of derivatives of phorbol and diacylglycerol (DAG) to establish the molecular features required for the activation of protein kinase C by a detailed comparison of the molecular geometries in these two classes of compounds. For DAG, a dihedral angle of about -60 degrees appears to be required for the oxygens at C2 and C3 because that angle is fixed at this value in phorbols. There is good agreement between the computed Boltzmann distribution for the O1-C1-C2-O2 dihedral angle and NMR results for the same angle in phospholipids, as obtained by others. A conformer of DAG is identified with dihedral angles corresponding to those of beta-phorbols. This conformer, however, is 3.2 kcal/mol above the global minimum found for DAG. The molecular geometry of this conformer is consistent with that of a number of active and inactive rigid analogues of DAG. The preferred conformation in beta-phorbol diesters is found to be stabilized by an antiparallel stacking of the ester carbonyl groups. The lack of activity of alpha-phorbol esters appears to be due to differences in a portion of the molecule containing the five-membered/seven-membered rings, which are far from the DAG-like end of the phorbol molecule. It is proposed that some of the biological activities of phorbol diesters may be due to this portion of the beta-phorbol molecule, which might represent a second active region, distinct from that resembling DAG.

Caenorhabditis elegans Proteins↗
PubMed1989

Conformational analysis of enkephalin analogs containing a disulfide bond. Models for delta- and mu-receptor opioid agonists.

Conformational analysis of the cyclic opioids H-Tyr-D-Pen-Gly-Phe-D-Pen-OH (DPDPE) and H-Tyr-D-Cys-Gly-Phe-D-Cys-OH (DCDCE) have been performed using the AMBER program. DPDPE is considerably more selective for delta-receptors than DCDCE. Using the RNGCFM program, a large number of ways were found to close the 14-membered disulfide-containing ring structure. However, intramolecular hydrogen bonds were only possible in gamma-turn and inverse gamma-turn conformations centered on the glycine residue which were associated with opposite chiralities of the disulfide bond. With the cyclic part of the molecules in either a gamma-turn or inverse gamma-turn, a systematic conformational analysis was performed on the tyrosine and phenylalanine sidechains. This showed that conformers with the tyrosine and phenylalanine phenyl rings in the vicinity of the disulfide bond were preferred due to attractive van der Waals forces. For DPDPE, however, this was only possible with a positive dihedral angle for the disulfide bond due to the presence of the beta-carbon methyls of Pen2. In contrast, these preferred conformers were possible with both chiralities of the disulfide bond in DCDCE. Conformational entropies and free energies were computed from the translational, rotational, and vibrational energy levels available to each conformer. The conformational entropies were found to vary significantly and to result in a re-ordering of the lowest energy minima. Based on these conformational differences in DPDPE and DCDCE and their differing pharmacological selectivities, tentative conformational preferences for delta- and mu-receptor opioid peptides are proposed.

Disulfides↗
PubMed1988

Receptor affinity, neurochemistry and behavioral characteristics of the enantiomers of thioridazine: evidence for different stereoselectivities at D1 and D2 receptors in rat brain.

The binding characteristics of the enantiomers of thioridazine were assessed in the brain of the rat using competitive radioreceptor assays with tritiated ligands selective for dopamine D1 (SCH-23390), D2 (spiperone), norepinephrine alpha-1 (prazosin) and muscarinic (quinuclinidinyl benzilate) receptors. (+)-Thioridazine was shown to have 2.7 and 4.5 times higher affinity than (-)-thioridazine for D2 and alpha-1 receptors, respectively. In contrast, (-)-thioridazine had 10 times higher affinity for the D1 receptor. Both enantiomers showed similar affinities for the muscarinic receptor. In a second experiment, thioridazine, dopamine, norepinephrine, serotonin and their metabolites were assayed in the brain of the rat after acute administration of the enantiomers of thioridazine and the assessment of catalepsy. (+)-Thioridazine was 4.1 times as potent as (-)-thioridazine in elevating the turnover of dopamine in the striatum, but neither enantiomer affected the other monoamines. The concentration of thioridazine and its metabolites in the brain, for a given dose, was similar for both enantiomers. (-)-Thioridazine induced slightly more catalepsy than (+)-thioridazine and appeared to be more toxic at large doses. While racemic thioridazine had an intermediate effect between that of its two enantiomers in the binding and neurochemical assays, it appeared to induce more catalepsy than either enantiomer, suggesting a synergistic effect in this behavioral assay. It was concluded that (+)- and (-)-thioridazine act as partially selective D2 and D1 antagonists, respectively. Therefore, clinical administration of only one enantiomer of thioridazine, rather than the currently prescribed racemate, may result in an improved therapeutic profile and so be worthy of further investigation.

Animals↗
PubMed1988

Neuropharmacology and stereochemistry of dopamine receptor agonist and antagonist enantiomeric pairs.

Neuropharmacological evaluation of the R and S isomers of 11-hydroxy-N-n-propylnoraporphine (11-OH-NPa) supports the impression that the 11-OH group in aporphines (analogous to the meta hydroxyl of dopamine, DA) is sufficient to confer high affinity and activity at DA receptors. As in the case of the catechol congeners, (R)-apomorphine (APO) and (R)-N-n-propylnorapomorphine (NPA), (R)-11-OH-NPa is a potent DA agonist while, like (S)-NPA, (S)-11-OH-NPa is a DA antagonist. Thus, (R) and (S)-11-OH-NPa are an additional pair of compounds in which one enantiomer is a DA agonist and the other an antagonist. Other analogous pairs are the enantiomers of 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP), and cis-1-methyl-5-hydroxy-2-(di-n-propylamino)tetralin (5-OH-MDAT). All contain a meta hydroxyphenyl, an N-n-propyl, and a phenethylamine moiety which can be superimposed in a consistent way to discriminate the DA agonists from the antagonists, with the key feature in this discrimination being the direction of the ammonium hydrogen. An energy penalty must be incurred by 3-PPP to assume the required conformations and it may account for the relatively low potency of the 3-PPP enantiomers. This analysis supports the view that rigid analogs of flexible compounds when "frozen" in their biologically active conformation exhibit higher affinity interactions with the receptor.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1987

A stereochemical and conformational model of dopaminergic agonist and antagonist activity: further evaluation.

Conformational energy calculations using the Molecular Mechanics II (MM2) program have been performed on 2-aminotetrahydronaphthalene (ATN) and 2-aminoindan derivatives which are active or inactive at dopamine receptors. The results were used to test a stereochemical and conformational model previously proposed for dopaminergic activity. The conformer predicted to be optimal for agonist activity was found to have relatively low energy (less than 1.5 kcal/mol) for all of the agonists examined. The model successfully: (1) explained the relative activity or inactivity of compounds such as cis- and trans-1-methyl-5-hydroxyl ATN derivatives and the corresponding cis- and trans-octohydrobenzo[f]quinolines; (2) predicted the more potent antipode of 2-aminoindan dopaminergic agonists; and (3) explained the structure--activity peculiarities of 3-(3-hydroxyphenyl)-N-alkylpiperidines in which the potency is increased for (3S)-isomers and decreased for (3R)-isomers when the N-alkyl group is greater than propyl. Predictions of postsynaptic dopaminergic antagonism were also made for some of the compounds. In agreement with previous conclusions, the inactivity of ATN derivatives with a 2-methyl or 5-propyl group was attributed to steric interference at the receptor since those groups did not have a significant conformational effect on the receptor ligand.

Models, Chemical↗
PubMed1987

Molecular geometries and steric energies of phorbol 10,11-diacetate and 1,2-diacetylglycerol molecules.

Protein kinase C, an enzyme that is stimulated physiologically by diacylglycerol (DAG) and phospholipids in the presence of Ca2+, is involved in a novel cellular signaling system that is activated by the binding of appropriate agonists to certain classes of receptors. Phorbol esters are tumor promoters that can replace DAG in the activation of protein kinase C. Molecular similarities between the two compounds have been proposed to be responsible for the capacity to activate the enzyme. We have studied the molecular geometries and conformational energies of DAGAc and PDAc using the Molecular Mechanics II program and parameter set developed by Allinger and Yuh (1980). This was done to establish whether conformers of the two compounds are geometrically similar and which hydroxyl group of the phorbol molecule corresponds to the C3 hydroxyl of DAG which must be unsubstituted for activation of protein kinase C.

Calorimetry↗
PubMed1986

Geometrical correspondence between phenazocine and the enkephalins.

Calculations have been performed on phenazocine using Allinger's MM2 (molecular mechanics II) program with full energy minimization. The N-phenethyl group was found to have considerable flexibility with a number of low-energy conformers. The best N-phenethyl axial conformer was 1.6 kcal/mol higher in energy than the best equatorial one. Calculations were also performed on the beta isomer of phenazocine with the result that the energy difference between the best equatorial and axial conformers rose to a substantial 4.6 kcal/mol. The hypothesis that opiate agonism requires an N substituent in the axial position does not appear to be consistent with the increased potency of beta isomers in which axial N substituents are thermodynamically more unstable. Comparisons have also been made between the low-energy conformers of phenazocine and those that have been observed or proposed for the enkephalins. One conformation of the tyrosine portion of the enkephalins that was observed by X-ray crystallography by Karle et al. was found to be a good fit to morphine-like opiates. The backbone conformer suggested by Gorin et al. was found to be the best fit to the two phenyl rings of phenazocine.

Enkephalins↗
PubMed1984

Preferred conformers for the pharmacologically typical and atypical antipodes of phenylmorphan opiates.

The conformational preferences of phenylmorphan have been determined by the MM2 (Molecular Mechanics II) program using full energy minimization. Chair-chair conformations of the cyclohexane and piperidine rings were preferred by 2.6 kcal/mol or more. With the preferred chair-chair conformation, three stable orientations of the phenyl ring were found with relative energies of 0.0, 1.0, and 1.2 kcal/mol. The barrier to rotation of the phenyl ring was computed to be 4 kcal/mol. The preferred phenyl orientation for the (+)-antipode was similar to that of morphine using a previously postulated molecular model for opiate substrates. This is consistent with the typical morphine-like pharmacological properties of this antipode. The preferred phenyl orientation of the atypical (-)-antipode appears to be most similar to the phenyl orientation that is invariably preferred by more active prodine antipodes. The preferred conformer was similar to the one observed by X-ray crystallography.

Molecular Conformation↗
PubMed1983

Conformational properties of butaclamol and isobutaclamol. Regularities in the structures of semirigid neuroleptics.

Conformational energy calculations have been performed on butaclamol and isobutaclamol using Allinger's MM2 (Molecular Mechanics II) program. Cis arrangements of rings D and E were found to be preferred by 1.4-1.9 kcal/mole for both compounds. Nevertheless, based on a molecular comparison with a number of semirigid neuroleptics, most notably loxapine and octoclothepin, it is suggested that trans arrangements are required for neuroleptic activity in the two compounds. However, trans conformer B of butaclamol, which was previously postulated as the biologically active form, was found to be 4.1 kcal/mole higher in energy, suggesting that it is less likely to play a significant pharmacological role. The biologically active forms are identified as trans conformer A for butaclamol and trans conformer B for isobutaclamol. Certain regularities in the structures of the semirigid neuroleptics are noted. It is also speculated that the cis conformers of protonated butaclamol may have unfavorable geometries for ion solvation, which would account for the anomalously low pKa measured for the compound. A similar explanation would also account for a trans conformer being found in the crystal structures of the bromide salts of butaclamol and dexaclamol.

Antipsychotic Agents↗
PubMed1982

Conformation-activity study of 4-phenylpiperidine analgesics.

A conformational study of various 4-phenylpiperidine analgesics (the prodines, ketobemidone, meperidine, and 1,3,4-trimethyl-4-phenylpiperidines) has been performed with Allinger's Molecular Mechanics II (MM2) program. Phenyl equatorial conformations were found to be preferred for the prodines, ketobemidone, and meperidine. For ketobemidone and meperidine, however, phenyl axial conformations were computed to be only 0.7 and 0.6 kcal/mol higher in energy. It was suggested that phenyl axial conformers can explain the potency-enhancing effect of a phenyl m-hydroxy group in these two compounds. In contrast, phenyl axial conformers were computed to be relatively unfavorable for the prodines, being 1.9, 2.8, and 3.4 kcal/mol higher in energy for 3-demethyl-, alpha-, and beta-prodine, respectively. In addition, relative concentrations of an analgesic conformation can be related to the potencies of the three prodines. A phenyl axial conformer was computed to be preferred by 0.7 kcal/mol for the 3-demethyl compound of 1,3,4-trimethyl-4-phenylpiperidine, with phenyl equatorial conformers preferred by 1.3 and 3.3 kcal/mol for the alpha and beta compounds. Phenyl axial conformers were unexpectedly found to be especially destabilized by a 3-methyl group in the beta configuration due to the steric crowding of the three piperidine substituents. Detailed comparisons were made between the computed structures and those observed by X-ray crystallography.

Analgesics↗
PubMedDate not supplied

Conformational analysis and a crystal structure of bupropion, an antidepressant with dopamine reuptake blocking activity.

A conformational analysis has been performed on the antidepressant bupropion using the MM3-92 program. In addition, the structure of the compound in the crystal state was obtained. There is good agreement between the computed global minimum and the structure observed by crystallography. The three-dimensional structure of the preferred conformer of bupropion is consistent with the three-dimensional structures of other dopamine reuptake blockers such as cocaine, CFT, and methylphenidate.

Antidepressive Agents, Second-Generation↗