Journal of medicinal chemistry
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The design and synthesis of potent thiocarbamate inhibitors for carboxypeptidase G2 are described. The best thiocarbamate inhibitor N-(p-methoxybenzenethiocarbonyl)amino-L-glutamic acid 6d, chosen for preliminary investigations of in vitro antibody-directed enzyme prodrug therapy (ADEPT), abrogated the cytotoxicity of a combination of A5B7-carboxypeptidase G2 conjugate and prodrug PGP (N-p-{N,N-bis (2-chloroethyl)amino}phenoxycarbonyl-L-glutamate) toward LS174T cells. This is the first report of a small-molecule enzyme inhibitor proposed for use in conjunction with the ADEPT approach.
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The design, synthesis, and biological evaluation of a novel series of 3-[2-(pyrrolidin-1-yl)ethyl]indoles with excellent selectivity for h5-HT1D (formerly 5-HT1Dalpha) receptors over h5-HT1B (formerly 5-HT1Dbeta) receptors are described. Clinically effective antimigraine drugs such as Sumatriptan show little selectivity between h5-HT1D and h5-HT1B receptors. The differential expression of h5-HT1D and h5-HT1B receptors in neural and vascular tissue prompted an investigation of whether a compound selective for the h5-HT1D subtype would have the same clinical efficacy but with reduced side effects. ⋯ The compounds were shown to be full agonists by measurement of agonist-induced [35S]GTPgammaS binding in CHO cells expressed with h5-HT receptors. This study suggests that the h5-HT1D and h5-HT1B receptors can be differentiated by appropriate substitution of the ligand in the region which binds to the aspartate residue and reveals a large binding pocket in the h5-HT1D receptor domain which is absent for the h5-HT1B receptor. The compounds described herein will be important tools to delineate the role of h5-HT1D receptors in migraine.
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Four new potential self-immolative prodrugs derived from phenol and aniline nitrogen mustards, four model compounds derived from their corresponding fluoroethyl analogues and two new self-immolative linkers were designed and synthesized for use in the suicide gene therapy termed GDEPT (gene-directed enzyme prodrug therapy). The self-immolative prodrugs were designed to be activated by the enzyme carboxypeptidase G2 (CPG2) releasing an active drug by a 1, 6-elimination mechanism via an unstable intermediate. Thus, N-[(4-¿[4-(bis¿2-chloroethyl¿amino)phenoxycarbonyloxy]methyl¿pheny l)c arbamoyl]-L-glutamic acid (23), N-[(4-¿[4-(bis¿2-chloroethyl¿amino)phenoxycarbonyloxy]methyl¿pheno xy) carbonyl]-L-glutamic acid (30), N-[(4-¿[N-(4-¿bis[2-chloroethyl]amino¿phenyl)carbamoyloxy]methyl¿+ ++phen oxy)carbonyl]-L-glutamic acid (37), and N-[(4-¿[N-(4-¿bis[2-chloroethyl]amino¿phenyl)carbamoyloxy]methyl¿+ ++phen yl)carbamoyl]-L-glutamic acid (40) were synthesized. ⋯ The phenylenediamine compounds were found to behave as prodrugs, yielding IC50 prodrug/IC50 drug ratios between 20- and 33-fold (for 37 and 40) and differentials of 12-14-fold between CPG2-expressing and control LacZ-expressing clones. The drugs released are up to 70-fold more potent than 4-[(2-chloroethyl)(2-mesyloxyethyl)amino]benzoic acid that results from the prodrug 4-[(2-chloroethyl)(2-mesyloxyethyl)amino]benzoyl-L-glutamic acid (CMDA) which has been used previously for GDEPT. These data demonstrate the viability of this strategy and indicate that self-immolative prodrugs can be synthesized to release potent mustard drugs selectively by cells expressing CPG2 tethered to the cell surface in GDEPT.
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On the basis of the structure-activity relationships of delta-opioid-selective peptide ligands and on a model of the proposed bioactive conformation for a potent and selective, conformationally constrained delta-opioid peptide ligand [(2S, 3R)-TMT1]DPDPE, a series of small organic peptide mimetic compounds targeted for the delta-opioid receptor have been designed, synthesized, and evaluated in radiolabeled ligand binding assays and in vitro bioassays. The new non-peptide ligands use piperazine as a template to present the most important pharmacophore groups, including phenol and phenyl groups and a hydrophobic moiety. This hydrophobic group was designed to mimic the hydrophobic character of the D-Pen residues in DPDPE, which has been found to be extremely important for increasing the binding affinity and selectivity of these non-peptide ligands for the delta-opioid receptor over the mu-opioid receptor. ⋯ Both enantiomers of SL-3111 were separated, and the (-)-isomer was shown to be the compound with the highest affinity for the delta-opioid receptor found in our study (IC50 = 4.1 nM), with a selectivity very similar to that observed for the racemic compound. The phenol hydroxyl group of SL-3111 turned out to be essential to maintain high affinity for the delta-opioid receptor, which also was observed in the case of the delta-opioid-selective peptide ligand DPDPE. Binding studies of SL-3111 and [p-ClPhe4]DPDPE on the cloned wild-type and mutated human delta-opioid receptors suggested that the new non-peptide ligand has a binding profile similar to that of DPDPE but different from that of (+)-4-[((alphaR)-alpha(2S,5R)-4-allyl-2, 5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC-80), another delta-opioid-selective non-peptide ligand.
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Comparative Study
Synthesis, opioid receptor binding, and bioassay of naltrindole analogues substituted in the indolic benzene moiety.
A series of analogues of the delta opioid receptor antagonist naltrindole (1) possessing a phenyl, phenoxy, or benzyloxy group at the 4'-, 5'-, 6'-, or - 7'-positions (4-15) and a 2-(2-pyridinyl)ethenyl group at the 5'-position (16) on the indolic benzene ring were synthesized through Fischer indolization of naltrexone. Compounds 4-16 were evaluated for their affinities in opioid receptor binding assays in rat or guinea pig brain membranes and for their opioid antagonist and agonist activities in vitro on the guinea pig ileum (GPI) and mouse vas deferens (MVD) preparations. All of the compounds displayed delta selectivity in binding to the delta, mu, and kappa opioid receptors. ⋯ The overall affinity and activity profile of compound 14 is, therefore, that of a nonpeptide ligand possessing mixed mu agonist/delta antagonist properties. Recently there has been considerable interest in such compounds possessing mu agonist/delta antagonist activities because of their potential therapeutic usefulness as analgesics with low propensity to produce tolerance and dependence side effects. The results of the present study suggest that morphinan derivatives related to 16 and 14 may provide useful leads for the development of potent nonpeptide ligands possessing delta agonist or mixed delta antagonist/mu agonist activities.