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1.
Biochemistry ; 42(11): 3214-23, 2003 Mar 25.
Article in English | MEDLINE | ID: mdl-12641452

ABSTRACT

The human immunodeficiency virus type I (HIV-1) transmembrane glycoprotein gp41 mediates viral entry through fusion of the target cellular and viral membranes. A segment of gp41 containing the sequence Glu-Leu-Asp-Lys-Trp-Ala has previously been identified as the epitope of the HIV-1 neutralizing human monoclonal antibody 2F5 (MAb 2F5). The 2F5 epitope is highly conserved among HIV-1 envelope glycoproteins. Antibodies directed at the 2F5 epitope have neutralizing effects on a broad range of laboratory-adapted HIV-1 variants and primary isolates. Recently, a crystal structure of the epitope bound to the Fab fragment of MAb 2F5 has shown that the 2F5 peptide adopts a beta-turn conformation [Pai, E. F., Klein, M. H., Chong, P., and Pedyczak, A. (2000) World Intellectual Property Organization Patent WO-00/61618]. We have designed cyclic peptides to adopt beta-turn conformations by the incorporation of a side-chain to side-chain lactam bridge between the i and i + 4 residues containing the Asp-Lys-Trp segment. Synthesis of extended, nonconstrained peptides encompassing the 2F5 epitope revealed that the 13 amino acid sequence, Glu-Leu-Leu-Glu-Leu-Asp-Lys-Trp-Ala-Ser-Leu-Trp-Asn, maximized MAb 2F5 binding. Constrained analogues of this sequence were explored to optimize 2F5 binding affinity. The solution conformations of the constrained peptides have been characterized by NMR spectroscopy and molecular modeling techniques. The results presented here demonstrate that both inclusion of the lactam constraint and extension of the 2F5 segment are necessary to elicit optimal antibody binding activity. The ability of these peptide immunogens to stimulate a high titer, peptide-specific immune response incapable of viral neutralization is discussed in regard to developing an HIV-1 vaccine designed to elicit a 2F5-like immune response.


Subject(s)
AIDS Vaccines/immunology , Antibodies, Monoclonal/immunology , HIV Envelope Protein gp41/immunology , HIV-1/immunology , AIDS Vaccines/chemistry , Amino Acid Sequence , Enzyme-Linked Immunosorbent Assay , HIV Envelope Protein gp41/chemistry , Models, Molecular , Molecular Sequence Data , Structure-Activity Relationship
2.
J Med Chem ; 42(11): 2007-20, 1999 Jun 03.
Article in English | MEDLINE | ID: mdl-10354409

ABSTRACT

A series of 4-(aminoethoxy)indoles 7 and a related series of 4-(aminoethoxy)indolones 8 were synthesized and evaluated for their affinity for both the high- and low-affinity agonist states (D2High and D2Low, respectively) of the dopamine (DA) D2 receptor. The 4-aminoethoxy derivatives (i.e., 7 and 8) were designed as bioisosteric analogues based on the phenol prototype 4. The indolones 8 were observed to have high affinity for the D2High receptor. Comparison of their previously reported chroman analogues with the more flexible 4-(aminoethoxy)indoles revealed the chroman analogues to be more potent, whereas little loss in D2High affinity was observed when comparing the 4-(aminoethoxy)indolones with their respective chroman analogues. Several regions of the phenoxyethylamine framework were modified and recognized as potential sites to modulate the level of intrinsic activity. A conformational analysis was performed and a putative bioactive conformation was proposed which fulfilled the D2 agonist pharmacophore criteria based on the McDermed model. Structure-activity relationships gained from these studies have aided in the synthesis of D2 partial agonists of varying intrinsic activity levels. These agents should be of therapeutic value in treating disorders resulting from hypo- and hyperdopaminergic activity, without the side effects associated with complete D2 agonism or antagonism.


Subject(s)
Dopamine Agonists/chemistry , Ethylamines/chemistry , Indoles/chemistry , Receptors, Dopamine D2/metabolism , Animals , Binding, Competitive , Corpus Striatum/metabolism , Dopamine Agonists/chemical synthesis , Dopamine Agonists/metabolism , Dopamine Agonists/pharmacology , Ethylamines/chemical synthesis , Ethylamines/metabolism , Ethylamines/pharmacology , Hippocampus/metabolism , In Vitro Techniques , Indoles/chemical synthesis , Indoles/metabolism , Indoles/pharmacology , Mice , Models, Molecular , Molecular Conformation , Motor Activity/drug effects , Radioligand Assay , Rats , Stereotyped Behavior/drug effects , Structure-Activity Relationship
3.
Bioorg Med Chem ; 7(11): 2453-6, 1999 Nov.
Article in English | MEDLINE | ID: mdl-10632054

ABSTRACT

Comparative molecular field analysis (CoMFA) has been applied to novel D2 partial agonists. Due to the predictability of the CoMFA model across different series of D2 partial agonists, we believe these compounds are binding to the D2 agonist receptor in the conformation and alignment described herein.


Subject(s)
Receptors, Dopamine D2/agonists , Models, Molecular , Structure-Activity Relationship
4.
J Biol Chem ; 273(25): 15458-63, 1998 Jun 19.
Article in English | MEDLINE | ID: mdl-9624131

ABSTRACT

A representative set of high resolution x-ray crystal structures of nonhomologous proteins have been examined to determine the preferred positions and orientations of noncovalent interactions between the aromatic side chains of the amino acids phenylalanine, tyrosine, histidine, and tryptophan. To study the primary interactions between aromatic amino acids, care has been taken to examine only isolated pairs (dimers) of amino acids because trimers and higher order clusters of aromatic amino acids behave differently than their dimer counterparts. We find that pairs (dimers) of aromatic side chain amino acids preferentially align their respective aromatic rings in an off-centered parallel orientation. Further, we find that this parallel-displaced structure is 0.5-0.75 kcal/mol more stable than a T-shaped structure for phenylalanine interactions and 1 kcal/mol more stable than a T-shaped structure for the full set of aromatic side chain amino acids. This experimentally determined structure and energy difference is consistent with ab initio and molecular mechanics calculations of benzene dimer, however, the results are not in agreement with previously published analyses of aromatic amino acids in proteins. The preferred orientation is referred to as parallel displaced pi-stacking.


Subject(s)
Protein Conformation , Proteins/chemistry , Crystallography, X-Ray , Databases, Factual , Dimerization , Histidine/chemistry , Models, Chemical , Phenylalanine/chemistry , Static Electricity , Tryptophan/chemistry , Tyrosine/chemistry
5.
Bioorg Med Chem Lett ; 8(3): 295-300, 1998 Feb 03.
Article in English | MEDLINE | ID: mdl-9871673

ABSTRACT

Described in this report is a systematic study which led to the identification of two new dopamine D2 partial agonists (5 and 17). Phenols 5 and 17 represent prototypes of two new classes of D2 partial agonists as well as templates for the future design of novel dopaminergic agents.


Subject(s)
Dopamine Agonists/chemistry , Phenols/chemistry , Piperazines/chemistry , Dopamine Agonists/pharmacology , Phenols/chemical synthesis , Phenols/pharmacology , Piperazines/chemical synthesis , Piperazines/pharmacology , Receptors, Dopamine D2/agonists , Structure-Activity Relationship
7.
IDrugs ; 1(7): 773-4, 1998 Nov.
Article in English | MEDLINE | ID: mdl-18465642
8.
J Med Chem ; 37(19): 3128-31, 1994 Sep 16.
Article in English | MEDLINE | ID: mdl-7932536

ABSTRACT

Choline acetyltransferase (ChAT) inhibitors related to trans-1-methyl-4- (1-naphthylvinyl)-pyridinium (NVP+) have been assumed to depend upon a nearly or completely planar conformation for their enzyme-inhibitor interaction. In an effort to investigate the geometries and preferred conformations for these compounds, geometry optimizations using the semiempirical molecular orbital method AM1 and a modified version of the molecular mechanics method MM2(92) have been carried out. The results indicate that the active inhibitors are either planar or nearly coplanar, lying in relatively flat potential wells in the vicinity of the corresponding planar structures. When nonplanarity is favored, one ring is twisted out of the plane by approximately 30 degrees. Where steric features significantly deter assumption of a nearly planar conformation, the analogs are inactive. The inactivity of analogs bearing tricyclic aryl groups appears to result from bulk-related hindrance to ChAT receptor binding rather than lack of coplanarity.


Subject(s)
Choline O-Acetyltransferase/antagonists & inhibitors , Naphthylvinylpyridine/analogs & derivatives , Naphthylvinylpyridine/chemistry , Chemical Phenomena , Chemistry, Physical , Models, Chemical , Molecular Conformation , Stereoisomerism , Structure-Activity Relationship , Thermodynamics
9.
Pharmacol Biochem Behav ; 40(3): 479-86, 1991 Nov.
Article in English | MEDLINE | ID: mdl-1806940

ABSTRACT

The compound 9-beta-hydroxy-hexahydrocannabinol [(-)-9 beta-OH-HHC] was designed to fit a combined theoretical profile of an analgesic cannabinoid (equatorial alcohol at C-9, phenol at C-1 and a C-3 side chain) with reduced psychoactivity (axial C-9 substituent which protrudes into the alpha face). (-)-9 beta-OH-HHC was synthesized by the addition of methyl Grignard to 9-oxo-11-nor-HHC. Its alpha epimer was obtained by the regiospecific epoxide ring opening of 9 alpha, 10 alpha-epoxy-HHC acetate. (-)-9 beta-OH-HHC and (-)-9 alpha-OH-HHC were each evaluated in a battery of tests in mice and were found to be 10-25 times less potent than (-)-trans-delta 9-tetrahydrocannabinol (delta 9-THC) in all tests including the tail flick test for antinociception (analgesia). Molecular mechanics calculations [MMP2(85)] revealed that, in the global minimum energy conformation of (-)-9 beta-OH-HHC, the axial methyl at C-9 protrudes into the alpha face of the molecule, while the axial hydroxyl at C-9 in (-)-9 alpha-OH-HHC protrudes into this same face. These calculations also identified a higher energy carbocyclic ring (twist) conformer of each in which there is no protrusion of a C-9 substituent of the carbocyclic ring into the alpha face. The minimal activity of both compounds is attributed to these higher energy forms.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Analgesics/pharmacology , Cannabinol/analogs & derivatives , Psychotropic Drugs/pharmacology , Animals , Body Temperature/drug effects , Cannabinol/chemistry , Cannabinol/pharmacology , Catalepsy/chemically induced , Male , Mice , Mice, Inbred ICR , Models, Molecular , Molecular Conformation , Motor Activity/drug effects , Reaction Time/drug effects , Stereoisomerism , Structure-Activity Relationship
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