Synthesis of Stereoisomeric Analogues of Endomorphin-2, H-Tyr-Pro-Phe-Phe-NH2, and Examination of Their Opioid Receptor Binding Activities and Solution Conformation

Okada, Yoshio; Fukumizu, Atsuko; Takahashi, M.; Shimizu, Yoshiro; Tsuda, Yuko; Yokoi, Toshio; Bryant, Sharon D.; Lazarus, Lawrence H.

doi:10.1006/bbrc.2000.3416

Cited by 49 publications

(65 citation statements)

References 16 publications

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“…This is consistent with the paucity of enzymes capable of hydrolysing peptide bonds with amino acids in the D-configuration [27]. Past attempts at exploiting this fact by substituting L-for D-amino acids in linear endomorphin derivatives were unsuccessful [3,4]. The substitutions resulted in binding affinities that were lower by up to three orders of magnitude, and structural comparisons with the native peptides suggested that the spatial arrangement of the side chains was unfavourable for receptor binding.…”

Section: Stability In Human Plasmasupporting

confidence: 59%

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Synthesis and Plasma Stability of Disulfide-Bridged Cyclic Endomorphin-1 Derivatives

Mansfeld¹,

Tóth²

2012

IJOC

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Endomorphin-1 is an endogenous opioid peptide that mediates pain relief through interaction with the µ-opioid receptor in the central nervous system. To enhance the metabolic stability of this tetrapeptide, cyclisation through the formation of a disulfide bridge between the side chains of cysteine residues added to the sequence was explored. A further increase in stability was achieved through N-terminal modification with lipoamino acid and lactose succinamic acid, and the inclusion of D-amino acids. The latter also provided an alternative spatial arrangement of the aromatic side chains. The lipidated cyclic derivatives were insoluble in aqueous buffer, however, the cyclic peptides and glycopeptides showed greatly improved stability towards enzymatic degradation in human plasma.

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Section: Stability In Human Plasmasupporting

confidence: 59%

“…These include the substitution of one or more amino acids in the sequence by D-amino acids [3][4][5], β-amino acids [6][7][8] and other non-natural amino acids, for example 2,6-dimethyl tyrosine [9,10], or the addition of sugar moieties or lipoamino acids [11,12].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Plasma Stability of Disulfide-Bridged Cyclic Endomorphin-1 Derivatives

Mansfeld¹,

Tóth²

2012

IJOC

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“…However, Phe 3 residue was quite essential because of its enantiomer in EM-2 (Table V, compound 68) reduced the m-affinity to a large extent. 32 A similar tendency can be seen in the case of EM-1, where the D-Trp 3 derivative possessed lower m-affinity than the parent peptide, while the inversion of the configuration of the N-and C-terminal aromatic amino acids caused a moderate alteration. 31 Similarly, replacing these residues with b-/homo-b-amino acids in EM-1 resultant peptides 69 and 70 also caused a significant loss of affinity.…”

Section: A Pro: a Spacer Or An Unusual Visa For Mor Selectivitysupporting

confidence: 56%

Endomorphins: potential roles and therapeutic indications in the development of opioid peptide analgesic drugs

Liu

Wang

2011

Medicinal Research Reviews

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The application of endomorphins as clinical available analgesic drugs has been impeded by their relatively poor receptor selectivity compared with alkaloid analgesics, rapid degradation in vivo, inefficient to penetrate the blood-brain barrier (BBB), and undesirable or toxic effects, such as acute tolerance and physical dependence, respiratory depression, and inhibition of gastrointestinal motility. Extensive studies have been performed so far striving to conquer these problems. In this article we review and discuss conformational and topographical modifications of the peptide amide bond and amino acid side groups to attain the most appropriate receptor binding affinity and high receptor selectivity; diverse strategies such as insertion of unnatural amino acids, covalent or noncovalent constraints as well as cyclization of linear peptides to enhance the enzymatic stability; designing of peptidomimetic ligands, glycopeptides, and N-terminal amidinationed analogues (such as incorporating guanidine into endomorphins) to penetrate the BBB. Also, several pertinent examples of bivalent and/or multivalent (such as mixed µ-agonist/δ-antagonist profile) compounds are discussed based on the existing literature and current data intending to give an insight into the development of opioid peptides expressing low tendency to produce acute tolerance and physical dependence.

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“…Recent studies indicated that [Sar 2 ] EM-2 showed enhanced stability in vitro (Janecka et al, 2006). In early work, it was recognized that replacement of L-Pro with D-Pro in EM-2 significantly attenuated the affinity (Okada et al, 2000) but produced more potent and longerlasting antinociception after ventricular administration (Shane et al, 1999). Here, we also introduced Gly as a spacer residue in position 3 with the hope of ensuring a ␤-turn conformation of the peptide.…”

mentioning

confidence: 99%

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

Liu²,

Yao³

et al. 2006

The Journal of Pharmacology and Experimental Therapeutics

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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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Synthesis of Stereoisomeric Analogues of Endomorphin-2, H-Tyr-Pro-Phe-Phe-NH2, and Examination of Their Opioid Receptor Binding Activities and Solution Conformation

Cited by 49 publications

References 16 publications

Synthesis and Plasma Stability of Disulfide-Bridged Cyclic Endomorphin-1 Derivatives

Synthesis and Plasma Stability of Disulfide-Bridged Cyclic Endomorphin-1 Derivatives

Endomorphins: potential roles and therapeutic indications in the development of opioid peptide analgesic drugs

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

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