The effect of halogenation on blood–brain barrier permeability of a novel peptide drug☆

Gentry, Cynthia L.; Egleton, Richard D.; Gillespie, T. J.; Abbruscato, Thomas J.; Bechowski, H.B; Hruby, Victor J.; Davis, Thomas P.

doi:10.1016/s0196-9781(99)00127-8

Cited by 119 publications

(83 citation statements)

References 42 publications

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“…The unique approaches undertaken here relied upon utilizing N-terminal cationization by guanylating and unnatural amino acid substitutions in position 2. In addition to the necessity for enzymic stability, it is widely accepted that peptides must cross the BBB to reach the CNS in an amount sufficient to act on appropriate receptors to exert the desired pharmacological effects (Gentry et al, 1999;Habgood et al, 2000). Recently, EM-1 and EM-2 have been demonstrated to have a saturable efflux system at the BBB (Kastin et al, 2001;Somogyvari-Vigh et al, 2004), which removes the peptides from the CNS, thus limiting brain uptake.…”

Section: Discussionmentioning

confidence: 99%

“…The second group is chloro-halogenation at the para-position of Phe 4 . As one might expect, cationic group addition would possibly decrease the lipophilicity of peptides (Hau et al, 2002), whereas previous studies have shown that addition of halogens to enkephalin analogs may enhance overall lipophilicity of the compound resulting in greater BBB permeability (Weber et al, 1991(Weber et al, , 1993Abbruscato et al, 1996;Gentry et al, 1999). Thus, to ensure the necessary lipophilicity for passive transport of the cationized EM-1 analogs through the BBB, structural modification was also made at the C terminus.…”

mentioning

confidence: 98%

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Utilization of Combined Chemical Modifications to Enhance the Blood-Brain Barrier Permeability and Pharmacological Activity of Endomorphin-1

Liu²,

Yao³

et al. 2006

J Pharmacol Exp Ther

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The endogenous -opioid receptor agonist, endomorphin (EM)-1, cannot be delivered into the central nervous system (CNS) in sufficient quantity to elicit analgesia when given systemically because it is severely restricted by the blood-brain barrier (BBB). To improve the physicochemical characteristics of EM-1 and subsequently achieve greater BBB permeation, we synthesized a series of EM-1 analogs by combining successful chemical modifications, including N-terminal cationization, Cterminal chloro-halogenation, and unnatural amino acid (D-Ala, Sar, and D-Pro-Gly) substitutions in position 2. Presently, their binding and bioassay activity, lipophilicity, stability, and antinociceptive activity were determined and compared. Guanidinoaddition and chloro-halogenation attenuated the -receptor affinity to some extent, but they demonstrated differences in the influence on stability. It appeared that guanidino-addition contributed to brain stability enhancement for the greater part, whereas chloro-halogenation together with amino acid substitutions in position 2 was of more importance for the stability enhancement in serum than in brain. Determination of the octanol/buffer coefficient revealed that chloro-halogenation did compromise the decreased lipophilicity caused by guanidinoaddition, and introduction of D-Ala as well as D-Pro-Gly, but not Sar, in place of L-Pro 2 , also increased the overall lipophilicity to some extent. Among the peptides tested, intracerebroventricular injection of guanidino-[D-Ala 2 , p-Cl-Phe 4 ]EM-1 showed the strongest analgesia, being 3 times more potent than the parent peptide. We also found that in comparison with EM-1, the four D-Ala-containing tetrapeptides and the chloro-halogenated DPro-Gly-containing pentapeptide elicited significant and prolonged central-mediated analgesia upon subcutaneous administration, indicating that more peptides reached the CNS, eliciting greater analgesic effect.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 98%

Utilization of Combined Chemical Modifications to Enhance the Blood-Brain Barrier Permeability and Pharmacological Activity of Endomorphin-1

Liu²,

Yao³

et al. 2006

J Pharmacol Exp Ther

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“…It has been shown that chloro and bromo substitution in the para position on phenylalanine increases hydrophobicity and blood-brain barrier permeability of a drug (Gentry et al, 1999). Likewise, halogenation of small molecules has been demonstrated to increase membrane permeation (Gerebtzoff et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

In Vitro Evaluation of Guanidine Analogs as Sigma Receptor Ligands for Potential Anti-Stroke Therapeutics

Behensky

Cortes-Salva

Seminerio

et al. 2012

J Pharmacol Exp Ther

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Currently, the only Food and Drug Administration-approved treatment of acute stroke is recombinant tissue plasminogen activator, which must be administered within 6 hours after stroke onset. The pan-selective s-receptor agonist N,N9-di-o-tolylguanidine (o-DTG) has been shown to reduce infarct volume in rats after middle cerebral artery occlusion, even when administered 24 hours after stroke. DTG derivatives were synthesized to develop novel compounds with greater potency than o-DTG. Fluorometric Ca 21 imaging was used in cultured cortical neurons to screen compounds for their capacity to reduce ischemia-and acidosis-evoked cytosolic Ca 21 overload, which has been linked to stroke-induced neurodegeneration. In both assays, migration of the methyl moiety produced no significant differences, but removal of the group increased potency of the compound for inhibiting acidosis-induced [Ca 21 ] i elevations. Chloro and bromo substitution of the methyl moiety in the meta and para positions increased potency by # 160%, but fluoro substitutions had no effect. The most potent DTG derivative tested was N,N9-di-p-bromo-phenyl-guanidine (p-BrDPhG), which had an IC 50 of 2.2 mM in the ischemia assay, compared with 74.7 mM for o-DTG. Microglial migration assays also showed that p-BrDPhG is more potent than o-DTG in this marker for microglial activation, which is also linked to neuronal injury after stroke. Radioligand binding studies showed that p-BrDPhG is a pan-selective s ligand. Experiments using the s-1 receptor-selective antagonist 1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine dihydrochloride (BD-1063) demonstrated that p-BrDPhG blocks Ca 21 overload via s-1 receptor activation. The study identified four compounds that may be more effective than o-DTG for the treatment of ischemic stroke at delayed time points.

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“…The N-methylation of hydrophobic amino acid residue decreases the bulkiness of peptides and improves the cell permeability to cross over the lipophilic cell membranes [22,49]. Halogenation improves the penetration ability of the aromatic substituent [16]. The extension of peptide sequence with appropriate substitution could induce the resistant mechanism against degradation and enhance the pharmacological properties [57,58].…”

Section: Functional Group Modifications and Toxicity Prediction Of Pementioning

confidence: 99%

Targeting the cyclin-binding groove site to inhibit the catalytic activity of CDK2/cyclin A complex using p27KIP1-derived peptidomimetic inhibitors

Arumugasamy

Tripathi

Shanmugam³

et al. 2014

J Chem Biol

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Functionally activated cyclin-dependent kinase 2 (CDK2)/cyclin A complex has been validated as an interesting therapeutic target to develop the efficient antineoplastic drug based on the cell cycle arrest. Cyclin A binds to CDK2 and activates the kinases as well as recruits the substrate and inhibitors using a hydrophobic cyclin-binding groove (CBG). Blocking the cyclin substrate recruitment on CBG is an alternative approach to override the specificity hurdle of the currently available ATP site targeting CDK2 inhibitors. Greater understanding of the interaction of CDK2/cyclin A complex with p27 (negative regulator) reveals that the LeuPhe-Gly (LFG) motif region of p27 binds with the CBG site of cyclin A to arrest the malignant cell proliferation that induces apoptosis. In the present study, Replacement with Partial Ligand Alternatives through Computational Enrichment (REPLACE) drug design strategies have been applied to acquire LFG peptide-derived peptidomimetics library. The peptidomimetics function is equivalent with respect to substrate p27 protein fashion but does not act as an ATP antagonist. The combined approach of molecular docking, molecular dynamics (MD), and molecular electrostatic potential and ADME/T prediction were carried out to evaluate the peptidomimetics. Resultant interaction and electrostatic potential maps suggested that smaller substituent is desirable at the position of phenyl ring to interact with Trp217, Arg250, and Gln254 residues in the active site. The best docked poses were refined by the MD simulations which resulted in conformational changes. After equilibration, the structure of the peptidomimetic and receptor complex was stable. The results revealed that the various substrate protein-derived peptidomimetics could serve as perfect leads against CDK2 protein.

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The effect of halogenation on blood–brain barrier permeability of a novel peptide drug☆

Cited by 119 publications

References 42 publications

Utilization of Combined Chemical Modifications to Enhance the Blood-Brain Barrier Permeability and Pharmacological Activity of Endomorphin-1

Utilization of Combined Chemical Modifications to Enhance the Blood-Brain Barrier Permeability and Pharmacological Activity of Endomorphin-1

In Vitro Evaluation of Guanidine Analogs as Sigma Receptor Ligands for Potential Anti-Stroke Therapeutics

Targeting the cyclin-binding groove site to inhibit the catalytic activity of CDK2/cyclin A complex using p27KIP1-derived peptidomimetic inhibitors

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