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A Karlén

Publications and source records attributed to A Karlén.

18 recordsLinked to original sources
PubMed1999

Angiotensin II analogues encompassing 5,9- and 5,10-fused thiazabicycloalkane tripeptide mimetics.

A simple experimental procedure on solid phase for the construction of new tripeptidic 5,9- and 5,10-fused thiazabicycloalkane scaffolds that adopt beta-turns has been developed. This N-terminal-directed bicyclization, relying on masked aldehyde precursors derived from glutamic acid as key building blocks, provides a complement to the related bicyclization previously reported, where an aspartic acid-derived precursor was employed to induce cyclization toward the C-terminal end of the peptide. Thus, the regioselectivity of the bicyclization can be altered simply by varying the chain length of the incorporated aldehyde precursor. Four analogues of the hypertensive octapeptide angiotensin II, comprising the new scaffolds in the 3-5- and 5-7-positions, were synthesized. One of these conformationally constrained angiotensin II analogues exhibited AT(1) receptor affinity (K(i) = 750 nM). Results from theoretical conformational analysis of model compounds of the bicyclic tripeptide mimetics are presented, and they demonstrate that subtle differences in geometry have a strong impact on the affinity to the AT(1) receptor.

Angiotensin II↗
PubMed1999

Inhibitors of the C(2)-symmetric HIV-1 protease: nonsymmetric binding of a symmetric cyclic sulfamide with ketoxime groups in the P2/P2' side chains.

Symmetric cyclic sulfamides, substituted in the P2/P2' position with functional groups foreseen to bind preferentially to the S2/S2' subsites of HIV-1 protease, have been prepared. Despite efforts to promote a symmetric binding, the sulfamides seemed prone to bind nonsymmetrically, as deduced from X-ray crystal structure analysis of one of the most potent inhibitors, possessing ketoxime groups in the P2/P2' side chains. Ab initio calculations suggested that the nonsymmetric conformation of the cyclic sulfamide scaffold had lower energy than the corresponding symmetric, cyclic urea-like conformation.

Crystallography, X-Ray↗
PubMed1999

Bicyclic tripeptide mimetics with reverse turn inducing properties.

Analogues of the hypertensive octapeptide angiotensin II, comprising novel constrained 5,8-bicyclic and 5,9-bicyclic tripeptide units adopting nonclassical beta-turn geometries, as deduced from theoretical conformational analysis, have been synthesized. Spontanous bicyclization upon acid-catalyzed deprotection of a model peptide, encompassing a protected omega-formyl alpha-amino acid in position 5 and cysteine residues in positions 3 and 7, revealed a strong preference for bicyclization toward the C-terminus. The bicyclic thiazolidine related angiotensin II analogues synthesized exhibited no affinity for the angiotensin II AT1 receptor.

Angiotensin II↗
PubMed1998

Correlation of human jejunal permeability (in vivo) of drugs with experimentally and theoretically derived parameters. A multivariate data analysis approach.

The effective permeability (Peff) in the human jejunum (in vivo) of 22 structurally diverse compounds was correlated with both experimentally determined lipophilicity values and calculated molecular descriptors. The permeability data were previously obtained by using a regional in vivo perfusion system in the proximal jejunum in humans as part of constructing a biopharmaceutical classification system for oral immediate-release products. pKa, log P, and, where relevant, log Pion values were determined using the pH-metric technique. On the basis of these experiments, log D values were calculated at pH 5.5, 6.5, and 7.4. Multivariate data analysis was used to derive models that correlate passive intestinal permeability to physicochemical descriptors. The best model obtained, based on 13 passively transcellularly absorbed compounds, used the variables HBD (number of hydrogen bond donors), PSA (polar surface area), and either log D5.5 or log D6.5 (octanol/water distribution coefficient at pH 5.5 and 6.5, respectively). Statistically good models for prediciting human in vivo Peff values were also obtained by using only HBD and PSA or HBD, PSA, and CLOGP. These models can be used to predict passive intestinal membrane diffusion in humans for compounds that fit within the defined property space. We used one of the models obtained above to predict the log Peff values for an external validation set consisting of 34 compounds. A good correlation with the absorption data of these compounds was found.

Humans↗
PubMed1997

Design, synthesis, and biological activities of four angiotensin II receptor ligands with gamma-turn mimetics replacing amino acid residues 3-5.

Disulfide cyclization is a powerful method for reducing the conformational space of a peptide. This in turn may enable the study of its bioactive conformation. Several analogues of angiotensin II (Ang II) containing a disulfide bridge between amino acids 3 and 5 have been reported. Among these the cyclic octapeptides c[Hcy3,5]-Ang II, c[Cys3,5]-Ang II, and c[Pen 3,5]-Ang II showed significant activity at Ang II receptors. We have performed conformational analysis studies using theoretical calculations and 1H-NMR spectroscopy on tripeptide model compounds of these cyclic octapeptides which show that the cyclic moieties of c[Cys3,5]-Ang II and c[Pen3,5]-Ang II preferentially assume an inverse gamma-turn conformation. On the basis of these results, we substituted amino acid residues 3-5 in Ang II with two different gamma-turn mimetics giving four diastereomeric Ang II analogues. Interestingly, two of these are equipotent to Ang II in binding to AT1 receptors. In the contractile test using rabbit aorta rings, one of the analogues is an agonist with full contractile activity approximately equipotent to c[Pen3,5]-Ang II but 300-fold less potent than Ang II. This low potency may suggest that Ang II does not adopt a gamma-turn in the 3-5 region when interacting with the receptor.

Angiotensin II↗
PubMed1997

Unexpected binding mode of a cyclic sulfamide HIV-1 protease inhibitor.

Two cyclic, C2-symmetric HIV-1 protease inhibitors, one sulfamide and one urea derivative, both comprising phenyl ether groups in the P1/P1' positions, were cocrystallized with HIV-1 protease, and the crystal structures were determined to 2.0 A resolution. The structure of the urea 2 showed a conformation similar to that reported for the related urea 3 by Lam et al., while the sulfamide 1 adopted an unanticipated conformation in which the P1' and P2' side chains were transposed.

Azepines↗
PubMed1997

Cyclic HIV-1 protease inhibitors derived from mannitol: synthesis, inhibitory potencies, and computational predictions of binding affinities.

Ten C2-symmetric cyclic urea and sulfamide derivatives have been synthesized from L-mannonic gamma-lactone and D-mannitol. The results of experimental measurement of their inhibitory potencies against HIV-1 protease were compared to calculated free energies of binding derived from molecular dynamics (MD) simulations. The compounds were selected, firstly, to enable elucidation of the role of stereochemistry for binding affinity (1a-d) and, secondly, to allow evaluation of the effects of variation in the link to the P1 and P1' phenyl groups on affinity (1a and 2-5). Thirdly, compounds with hydrogen bond-accepting or-donating groups attached to the phenyl groups in the P2 and P2' side chains (6 and 7) were selected. Binding free energies were estimated by a linear response method, whose predictive power for estimating binding affinities from MD simulations was demonstrated.

Anti-HIV Agents↗
PubMed1994

Dopamine D2 receptor agonists: an analysis of indirect models.

To evaluate a previously suggested "dopamine (DA) D2 receptor agonist pharmacophore model" the N-propyl derivatives (1S,2S)-5-hydroxy-1-methyl-2-propylaminotetralin [(1S,2S)-3)] and trans-(+/-)-5-hydroxy-3-methyl-2-propylaminotetralin [(+/-)-4] were synthesized and their conformational preferences were studied by molecular mechanics calculations. The new compounds were evaluated for affinity to striatal DA D2 receptors labelled by [3H]spiroperidol and [3H]N-propylnorapomorphine. In comparison to the corresponding N,N-dipropyl derivatives, compounds (1S,2S)-3 and (+/-)-4 more readily adopt pharmacophore conformations and have higher affinity for DA D2 receptors. Thus, the pharmacophore model for C5-oxygenated 2-aminotetralins appears to be accurate. The DA D2 receptor binding affinities of a series of C1- or C3-methyl substituted 5- or 7-hydroxy-2-dipropylaminotetralin derivatives were also determined to enable a comparison of three different modes of superposition, of 7- and 5-hydroxylated 2-aminotetralin derivatives. The results show that the relative spatial positions of the C1- and C3-methyl groups resulting from the various superpositions of 5- and 7-hydroxylated regioisomers differ and the fact that the bulk of a methyl group may be readily accepted by the receptor does not necessarily indicate that additional bulk may be tolerated. Consequently, a definitive choice of mode of superposition of 5- and 7-hydroxylated regioisomers can not be made at present and has to wait until the binding site itself has been better defined.

Animals↗
PubMed1993

Conformational properties of melatonin and two conformationally restricted agonists: a molecular mechanics and NMR spectroscopic study.

The hormone melatonin (N-acetyl-5-methoxytryptamine) has been implicated in the regulation of several neural and endocrine processes that are cued by the daily change in photoperiod. The conformational properties of melatonin and two conformationally restricted agonists, 8-methoxy-2-acetamidotetralin and cis-1-methyl-8-methoxy-2-acetamidotetralin, were examined as a starting point for SAR studies. The conformational analysis was carried out by means of molecular mechanics calculations (MM2-85 force field) using a step-wise build-up procedure and the molecular modelling program MacroModel (which has a modified version of the MM2 force field) for Monte Carlo and systematic tree searches. NMR spectroscopy was used to evaluate the conformational behaviour in solution. The three search methods were complementary and produced a good description of the conformational characteristics. The two force fields produced different geometries of some low energy conformations and also different relative steric energies. When using the MM2-85 force field, an intra-molecular interaction between the amide-H and the aromatic system lowers the relative energies of several conformations of both melatonin and the 2-amidotetralins. However, NMR experiments indicated that these interactions, which may be quite important in vacuo, are not important in solution.

Computer Simulation↗
PubMed1989

Topography and conformational preferences of 6,7,8,9-tetrahydro-1-hydroxy-N,N-dipropyl-5H-benzocyclohepten-6- ylamin e. A rationale for the dopaminergic inactivity.

In an attempt to rationalize the inability of phenolic benzocycloheptenylamines to activate dopamine (DA) D2 receptors, we have studied the conformational preferences and topography of 6,7,8,9-tetrahydro-1-hydroxy-N,N-dipropyl-5H-benzocyclohepten-6-++ +ylamine (1). Preferred conformations of 1 have been defined by use of experimental (NMR spectroscopic studies) and theoretical (MMP2, AM1, and MNDO calculations) methods. Topographical characteristics were studied by use of molecular graphics. Results from the MMP2 calculations agree with those from the AM1 calculations and the NMR spectroscopic study--1 seems to preferentially adopt chair conformations with a pseudoequatorial C6 substituent. The MNDO calculations, however, produced results that deviate considerably from those of the other theoretical methods. Most likely, pharmacophore conformations of (S)-1 do not present volumes that are part of the DA D2 receptor essential volume. Therefore, it appears that the energy penalty paid by the pharmacophore conformations is responsible for the dopaminergic inactivity of (S)-1. The inactivity of (R)-1 may be due to high energies of pharmacophore conformations and/or to steric factors since these conformations produce large excess volumes that may be part of the DA D2 receptor essential volume. The model used in the present report--a flexible pharmacophore combined with a partial receptor-excluded volume--might be used in the design of new DA D2 receptor agonists.

Benzocycloheptenes↗
PubMed1988

Structural factors of importance for 5-hydroxytryptaminergic activity. Conformational preferences and electrostatic potentials of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and some related agents.

The conformational characteristics of two series of 5-hydroxytryptamine (5-HT) receptor agonists, monophenolic N,N-dialkylated 2-aminotetralins and trans-2-phenylcyclopropylamines, have been studied by a combination of experimental (NMR spectroscopy) and theoretical (molecular mechanics and MNDO calculations) methods. In addition, molecular electrostatic potentials have been calculated for selected conformations and the absolute configuration of the potent 5-HT-receptor agonist (+)-cis-8-hydroxy-1-methyl-2-(di-n-propylamino)tetralin has been determined, by X-ray crystallography of the synthetic precursor, to be 1S,2R. Results obtained are discussed in terms of conformational, steric, and electronic requirements for 5-HT-receptor activation. It is suggested that different conformations of the 5-HT-receptor agonists (1R,2S)-2-(2-hydroxyphenyl)-N,N-di-n-propylcyclopropylamine [(1R,2S)-4] and its 3-hydroxy isomer (1R,2S)-5 are able to activate 5-HT receptors. The strongly increased stereoselectivity of 2, 4, and 5 as compared to that of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 1) is rationalized on the basis of steric factors. Conformational factors appear to be responsible for the inability of the trans-C1-methyl-substituted derivative of 1 to activate 5-HT receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1988

Central dopaminergic and 5-hydroxytryptaminergic effects of C3-methylated derivatives of 8-hydroxy-2-(di-n-propylamino)tetralin.

A number of stereochemically well defined C3-methylated derivatives of the potent 5-hydroxytryptamine (5-HT) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) have been synthesized, and their stereochemical characteristics have been studies by use of NMR spectroscopy, X-ray crystallography, and molecular mechanics calculations. The compounds were tested for activity at central 5-HT and dopamine (DA) receptors, by use of biochemical and behavioral tests in rats. In addition, the ability of the cis- and trans-8-hydroxy-3-methyl-2-(di-n-propylamino)tetralins (15 and 11) to displace [3H]-8-OH-DPAT from 5-HT1A binding sites was evaluated. The stereoselectivity of the interaction of 11 and 15 with 5-HT receptors was much greater than that of 8-OH-DPAT. Observed rank order of potencies in the 5-HT1A binding assay corresponds to that in the in vivo biochemical assay.

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

C3-methylated 5-hydroxy-2-(dipropylamino)tetralins: conformational and steric parameters of importance for central dopamine receptor activation.

C3-Methyl-substituted derivatives of the potent dopamine (DA) receptor agonist 5-hydroxy-2-(di-n-propylamino)tetralin (5-OH-DPAT) have been synthesized and their conformational preferences have been studied by use of NMR spectroscopy, X-ray crystallography, and molecular mechanics calculations (MMP2). The compounds were tested for activity at central DA receptors, by use of biochemical and behavioral tests in rats. (2R,3S)-5-Hydroxy-3-methyl-2-(di-n-propylamino)tetralin [(-)-8] was demonstrated to be a highly potent DA receptor agonist, while the other new compounds were of low potency or inactive. Results obtained confirmed the hypothesis that the tetralin inversion angle phi and the direction of the N-electron pair (N-H) tau N are conformational parameters of critical importance for DA D2 receptor activation in the 2-aminotetralin series. The high potency of (-)-8 allowed an extension of a previously defined "partial DA D2 receptor excluded volume".

Animals↗
PubMed1987

C1- and C3-methyl-substituted derivatives of 7-hydroxy-2-(di-n-propylamino)tetralin: activities at central dopamine receptors.

C1- and C3-methyl-substituted derivatives of the potent dopamine (DA) receptor agonist 7-hydroxy-2-(di-n-propylamino)tetralin (7-OH-DPAT) have been synthesized, and their conformational preferences have been studied by use of NMR spectroscopy, X-ray crystallography, and molecular mechanics (MMP2) calculations. The compounds were tested for activity at central DA receptors, by use of biochemical and behavioral tests in rats. (1S,2R)-7-Hydroxy-1-methyl-2-(di-n-propylamino)tetralin [(+)-10] was demonstrated to be sevenfold less potent than (2R)-7-OH-DPAT as a DA receptor agonist. The other new compounds were of lower potency or inactive.

Animals↗
PubMed1986

Conformational analysis of the dopamine-receptor agonist 5-hydroxy-2-(dipropylamino)tetralin and its C(2)-methyl-substituted derivative.

The conformational preferences of the dopamine (DA) receptor agonist 5-hydroxy-2-(di-n-propylamino)tetralin (1) and the DA-inactive 5-hydroxy-2-methyl-2-(di-n-propylamino)tetralin (2) have been studied by use of molecular mechanics (MMP2) calculations and NMR spectroscopy. A good agreement is demonstrated between the experimentally determined (by NMR) and the calculated (by MMP2) conformational distribution of 1 and 2. In addition, there is a good agreement between bond distances and bond angles in the X-ray structure of the hydrobromide of 1 and those in the corresponding MMP2 conformation. Results obtained demonstrate that the energetically preferred conformations of 1 and 2 are different: Compound 1 preferentially adopts half-chair conformations with a pseudoequatorial nitrogen substituent whereas the low-energy conformations of compound 2 have a pseudoaxial nitrogen substituent. However, the results also indicate that the difference in conformational preferences is too small to account for the dopaminergic inactivity of 2. Therefore it is suggested that the steric bulk of the C(2)-methyl group per se prevents a proper alignment of (2S)-2 with DA receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1986

Dopaminergic 2-aminotetralins: affinities for dopamine D2-receptors, molecular structures, and conformational preferences.

A combination of X-ray crystallography, NMR spectroscopy, and molecular mechanics (MMP2) calculations was used to determine the three-dimensional structures and conformational preferences of the enantiomers of 5-hydroxy-2-(di-n-propylamino)tetralin and their C1-methylated derivatives. In addition, the affinities of the compounds for striatal 3H-spiroperidol- and 3H-N-n-propylnorapomorphine-binding sites were determined. In the present series, the dopamine D2-receptor agonists have the S-configuration at the nitrogen-bearing carbon (C2), whereas the only established D2-receptor antagonist, 1S,2R-5-hydroxyl-1-methyl-2-(di-n-propylamino)tetralin (1S,2R-UH-242), has the opposite absolute configuration at C2. Two conformational parameters, the tetralin inversion angle (phi) and the dihedral angle tau(C1, C2, N, N-H or electron pair) (tau N), are shown to be critical for D2-receptor agonism; phi values around 0 degrees and tau N values around 60 degrees appear to be optimal. The low D2-affinity of 1S,2S-5-hydroxyl-1-methyl-2-(di-n-propylamino)tetralin seems to be related to its inability to assume a low-energy "D2-receptor agonistic conformation." It is noted that the common structural denominator between the D2-receptor antagonists 1S,2R-UH-242 and 6aS-apomorphine is their inability to assume "dopamine D2-receptor agonistic nitrogen electron pair orientations."

Apomorphine↗