Conformation-activity relationships of opioid peptides with selective activities at opioid receptors

Hruby, Victor J.; Agnes, Richard S.

doi:10.1002/(sici)1097-0282(1999)51:6<391::aid-bip3>3.0.co;2-x

Cited by 86 publications

(25 citation statements)

References 87 publications

(68 reference statements)

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“…Furthermore, these sites of cyclization are consistent with cyclic peptide ligands for opioid receptors, particularly to DPDPE in which positions 2 and 5 were substituted with D-Pen [30]. Also this design retains the free N-terminal Tyr 1 , which is important for agonist activity at opioid receptors [8,18,28]. From the perspective of the CCK receptors, the Phe 8 C-terminal end was not used for cyclization since Phe 8 is important for the recognition of peptide ligands at CCK receptors, much like other reported cyclic analogues of CCK-8 [9,10].…”

Section: Design Of Cyclic Peptidessupporting

confidence: 54%

Structure–activity relationships of bifunctional cyclic disulfide peptides based on overlapping pharmacophores at opioid and cholecystokinin receptors

et al. 2008

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Prolonged opioid exposure increases the expression of cholecystokinin (CCK) and its receptors in the central nervous system, where CCK may attenuate the antinociceptive effects of opioids. The complex interactions between opioid and CCK may play a role in the development of opioid tolerance. We designed and synthesized cyclic disulfide peptides and determined their agonist properties at opioid receptors and antagonist properties at CCK receptors. Compound 1 (Tyr-c[DCys-Gly-Trp-Cys]-Asp-Phe-NH 2 ) showed potent binding and agonist activities at δ and µ opioid receptors while displaying some binding to CCK receptors. The NMR structure of the lead compound displayed similar conformational features of opioid and CCK ligands.

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Section: Design Of Cyclic Peptidessupporting

confidence: 54%

Structure–activity relationships of bifunctional cyclic disulfide peptides based on overlapping pharmacophores at opioid and cholecystokinin receptors

et al. 2008

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“…The majority of opioid peptides contain the core tetrapeptide, Tyr-Gly-Gly-Phe, important for high affi nity and bioactivity. 5 In frog-skin-derived peptides the " Gly-Gly " motif is substituted by D-stereoisomers of Ala, Met, or Ile. Pharmacological studies indicate that no family of endogenous peptides is exclusively associated with a particular receptor type.…”

Section: Introductionmentioning

confidence: 99%

“…To improve ligand selectivity, conformational and topographical constraints have been incorporated into the peptide ligands, and several highly selective cyclic peptides have been generated. 5 The fi rst highly d -selective enkephalin …”

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confidence: 99%

Homology modeling of opioid receptor-ligand complexes using experimental constraints

Pogozheva

Przydzial

Mosberg

2005

AAPS J

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A BSTRACTOpioid receptors interact with a variety of ligands, including endogenous peptides, opiates, and thousands of synthetic compounds with different structural scaffolds. In the absence of experimental structures of opioid receptors, theoretical modeling remains an important tool for structurefunction analysis. The combination of experimental studies and modeling approaches allows development of realistic models of ligand-receptor complexes helpful for elucidation of the molecular determinants of ligand affi nity and selectivity and for understanding mechanisms of functional agonism or antagonism. In this review we provide a brief critical assessment of the status of such theoretical modeling and describe some common problems and their possible solutions. Currently, there are no reliable theoretical methods to generate the models in a completely automatic fashion. Models of higher accuracy can be produced if homology modeling, based on the rhodopsin X-ray template, is supplemented by experimental structural constraints appropriate for the active or inactive receptor conformations, together with receptor-specifi c and ligand-specifi c interactions. The experimental constraints can be derived from mutagenesis and cross-linking studies, correlative replacements of ligand and receptor groups, and incorporation of metal binding sites between residues of receptors or receptors and ligands. This review focuses on the analysis of similarity and differences of the refi ned homology models of m , d , and k -opioid receptors in active and inactive states, emphasizing the molecular details of interaction of the receptors with some representative peptide and nonpeptide ligands, underlying the multiple modes of binding of small opiates, and the differences in binding modes of agonists and antagonists, and of peptides and alkaloids.K EYWORDS: ligand docking , modeling , opioid receptors , opioid ligands , pharmacophore model INTRODUCTIONClinical interest in opioid receptors (ORs) is related to the development of strong analgesics without potential for abuse or adverse side effects. This task, however, cannot be accomplished without understanding the differences in the OR subtypes as well as the modes of interactions of drugs/ ligands with these receptors.Research on ORs was signifi cantly advanced by the cloning of d -opioid (DOR), m -opioid (MOR), and k -opioid (KOR) receptors in the early 1990s. 1 , 2 Sequence comparison confi rmed that ORs belong to the rhodopsin-like family of G-protein-coupled receptors (GPCRs). 1 ORs are composed of a core domain of 7 transmembrane (TM) a -helices and an adjacent, peripheral helix 8 (IL4), are connected by 3 extracellular (EL1, EL2, EL3) and 3 intracellular (IL1, IL2, IL3) loops, and contain glycosylated N-terminal and palmitoylated C-terminal domains of different sizes. ORs demonstrate high sequence identity in their TM domain (73%-76%) and in ILs (63%-66%) and large divergence in N-and C-terminal domains and ELs (34%-40% identity). ORs are activated by either endogenous peptides o...

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“…For example, rational peptide ligand designs, in contrast with high throughput screening of randomly varied ligand libraries (Zysk and Baumbach, 1998), are dominated by pharmacophores, three-dimensional models of their putative active or regulatory binding sites (Guner, 1999;Hruby and Agnes, 1999;Takeuchi et al, 1998). Similarly, polypeptide-protein and protein-protein interactions of physically characterized structures are explored using docking algorithms (Janin, 1995;Makino and Kuntz, 1997;Sandak et al, 1998;Stahl and Bohm, 1998).…”

Section: Introductionmentioning

confidence: 99%

Cellular and Behavioral Effects of D2 Dopamine Receptor Hydrophobic Eigenmode-Targeted Peptide Ligands

Mandell

Selz

Owens

et al. 2003

Neuropsychopharmacol

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Patterns in G-protein-coupled receptors' hydrophobically transformed amino-acid sequences can be computationally characterized as hierarchies of autocorrelation waves, 'hydrophobic eigenmodes,' using autocovariance matrix decomposition and all poles power spectral and wavelet transformations. L-or D-amino acid (retro-inverso) 12-18 residue peptides targeting these modes can be designed using eigenvector templates derived from these computations. In all, 12 human long-form D 2 dopamine receptor eigenmode-targeted 15 mer peptides were designed, synthesized, and shown to modulate and/or indirectly activate the extracellular acidification response, EAR, in stably receptor-transfected CHO and LtK cells, with an 83% hit rate. Representative L-and D-amino-acid retro-inverso peptides injected bilaterally in the nucleus accumbens demonstrated changes in rat exploratory behavior and prepulse inhibition similar to those observed following parenteral amphetamine. In contrast with geometric models used for ligand design, such as pharmacophores, the hydrophobic eigenmode approach to lead modulatory peptide design targets hydrophobic eigenmode-bearing subsequences, including those not visible from X-ray and NMR studies such as extracellular segments and loops.

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Conformation-activity relationships of opioid peptides with selective activities at opioid receptors

Cited by 86 publications

References 87 publications

Structure–activity relationships of bifunctional cyclic disulfide peptides based on overlapping pharmacophores at opioid and cholecystokinin receptors

Structure–activity relationships of bifunctional cyclic disulfide peptides based on overlapping pharmacophores at opioid and cholecystokinin receptors

Homology modeling of opioid receptor-ligand complexes using experimental constraints

Cellular and Behavioral Effects of D2 Dopamine Receptor Hydrophobic Eigenmode-Targeted Peptide Ligands

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