The invention provides novel potent inhibitors of the ternary
protein complex of nNOS, PSD-95, and the
NMDA receptor and pharmaceutical compositions comprising the inhibitors for prophylaxis and / or treatment of excitotoxic-related
disease and
chronic pain conditions in a subject. The inhibitors are dimeric PSD-95 inhibitors comprising a first
peptide or
peptide analogue linked to a second
peptide or peptide analogue by a
linker, wherein the first and the second peptide or peptide analogue comprise at least four
amide-bonded residues having a sequence YTXV or YSXV, wherein a. Y is selected from among E, Q, and A, or an analogue thereof, and b. X is selected from among A, Q, D, N, N-Me-A, N-Me-Q, N-Me-D, and N-Me-N or an analogue thereof, and wherein a
Cell Penetrating
Peptide (CPP) is linked to the
linker or to an
amino acid side chain of the first and second peptide or peptide analogue. The
linker can be a PEG or NPEG linker.