Cellular and behavioral effects of D2 dopamine receptor hydrophobic eigenmode-targeted peptide ligands.
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.
Mandell
Arnold J
AJ
Cielo Institute, 486 Sunset Drive, Asheville, NC 28804-3727, USA. mandell@cieloinstitute.org
Selz
Karen A
KA
Owens
Michael J
MJ
Kinkead
Becky
B
Shlesinger
Michael F
MF
Gutman
David A
DA
Arguragi
Vani
V
D000595:Amino Acid Sequence; D000818:Animals; D006224:Cricetinae; D004298:Dopamine / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008969:Molecular Sequence Data; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D010455:Peptides / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism*
D008024:Ligands; D010455:Peptides; D017448:Receptors, Dopamine D2; D004298:Dopamine