Development of neuropeptide drugs that cross the blood-brain barrier

Egleton, Richard D.; Davis, Thomas P.

doi:10.1007/bf03206641

Cited by 20 publications

(25 citation statements)

References 130 publications

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“…37,61,62 Lipoamino acids have been introduced to a number of neuropeptide analogues including somatostatin, 46,63 conotoxins, 47 or opioid peptides. 64 A reversible lipidization strategy was successfully applied to improve bioavailability of opioid peptides 65 or octreotide.…”

Section: Discussionmentioning

confidence: 99%

Design, Synthesis, and Characterization of High-Affinity, Systemically-Active Galanin Analogues with Potent Anticonvulsant Activities

et al. 2008

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Galanin is an endogenous neuropeptide that modulates seizures in the brain. Because this neuropeptide does not penetrate the blood-brain barrier, we designed truncated galanin analogues in which nonessential amino acid residues were replaced by cationic and/or lipoamino acid residues. The analogues prevented seizures in the 6 Hz mouse model of epilepsy following intraperitoneal administration. The most active analogue, Gal-B2 (NAX 5055), contained the -Lys-Lys-Lys(palmitoyl)-Lys-NH(2) motif and exhibited high affinity for galanin receptors (K(i) = 3.5 nM and 51.5 nM for GalR1 and GalR2, respectively), logD = 1.24, minimal helical conformation and improved metabolic stability. Structure-activity-relationship analysis suggested that cationization combined with position-specific lipidization was critical for improving the systemic activity of the analogues. Because the anticonvulsant activity of galanin is mediated by the receptors located in hippocampus and other limbic brain structures, our data suggest that these analogues penetrate into the brain. Gal-B2 may lead to development of first-in-class antiepileptic drugs.

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Section: Discussionmentioning

confidence: 99%

Design, Synthesis, and Characterization of High-Affinity, Systemically-Active Galanin Analogues with Potent Anticonvulsant Activities

et al. 2008

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“…It tends to establish a concentration or chemical potential equilibrium of substances, is non-saturable, and requires no energy [180]. On the other hand, this type of diffusion is usually restricted to substances with higher lipophilicity and small size.…”

Section: Types Of Molecular Transportmentioning

confidence: 98%

Drug-Loaded Nanocarriers: Passive Targeting and Crossing of Biological Barriers

Rabanel

Aoun²,

Elkin³

et al. 2012

CMC

160

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Poor bioavailability and poor pharmacokinetic characteristics are some of the leading causes of drug development failure. Therefore, poorly-soluble drugs, fragile proteins or nucleic acid products may benefit from their encapsulation in nanosized vehicles, providing enhanced solubilization, protection against degradation, and increased access to pathological compartments. A key element for the success of drug-loaded nanocarriers is their ability to either cross biological barriers themselves, or allow loaded drugs to traverse them to achieve optimal pharmacological action at pathological sites. Depending on the mode of administration, nanocarriers may have to cross different physiological barriers in their journey towards their target. In this review, the crossing of biological barriers by passive targeting strategies will be presented for intravenous delivery (vascular endothelial lining, particularly for tumor vasculature and blood brain barrier targeting), oral administration (gastrointestinal lining), and upper airway administration (pulmonary epithelium). For each specific barrier, background information will be provided on the structure and biology of the tissues involved as well as available pathways for nano-objects or loaded drugs (diffusion and convection through fenestration, transcytosis, tight junction crossing, etc.). The determinants of passive targeting - size, shape, surface chemistry, surface patterning of nanovectors - will be discussed in light of current results. Perspectives on each mode of administration will be presented. The focus will be on polymeric nanoparticles and dendrimers, although advances in liposome technology will be also reported as they represent the largest body in the drug delivery literature.

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“…These include increasing the lipophylicity of the peptide compound, glycosylation, use of liposomes or nanoparticles, and molecular Trojan horse approaches (for reviews see [186][187][188]). One promising mode of parenteral drug delivery which offers a means of circumventing the BBB is intranasal administration.…”

Section: Obstacles Facing the Clinical Application Of Npy Receptor LImentioning

confidence: 99%

Clinical Potential of Neuropeptide Y Receptor Ligands in the Treatment of Epilepsy

Meurs¹,

Clinckers²,

Ebinger³

et al. 2007

CTMC

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A substantial amount of experimental evidence implicates neuropeptide Y (NPY) in the pathophysiology of epilepsy. Over the past 20 years, remarkable progress has been made in unraveling the mechanisms and receptors involved in the anticonvulsant effect of this abundantly expressed neuropeptide. Activation of Y(2) and/or Y(5) receptors and blockade of Y(1) receptors in the central nervous system suppresses seizures in a variety of animal seizure models. Orally available, brain penetrating Y(2) and/or Y(5) agonists, and possibly Y(1) antagonists, may therefore constitute a novel class of antiepileptic drugs, which could greatly benefit patients with medically refractory epilepsy. Significant progress has been made in identifying non-peptidergic Y(1) antagonists that fulfill these criteria, but suitable Y(2) and/or Y(5) agonists have proven to be more elusive. Innovative oral and parental drug delivery strategies which are currently under development may offer a means of using the more readily available peptidergic NPY receptor ligands in a clinical setting. Finally, gene therapy, antisense probes or RNA interference strategies which alter the expression of NPY or its receptors in specific brain regions may also be of use in the treatment of epilepsy, but will probably benefit a smaller subgroup of epilepsy patients, since they typically require an invasive procedure.

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Development of neuropeptide drugs that cross the blood-brain barrier

Cited by 20 publications

References 130 publications

Design, Synthesis, and Characterization of High-Affinity, Systemically-Active Galanin Analogues with Potent Anticonvulsant Activities

Design, Synthesis, and Characterization of High-Affinity, Systemically-Active Galanin Analogues with Potent Anticonvulsant Activities

Drug-Loaded Nanocarriers: Passive Targeting and Crossing of Biological Barriers

Clinical Potential of Neuropeptide Y Receptor Ligands in the Treatment of Epilepsy

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