Rapastinel: Molecular Structure

Molecular Structure and Properties#

Rapastinel (GLYX-13) is a synthetic amidated tetrapeptide with the sequence threonine-proline-proline-threonine-amide (Thr-Pro-Pro-Thr-NH2). It has a molecular weight of 413.47 Da, molecular formula C18H31N5O6, and CAS number 117928-94-6. The compound was originally identified through structure-activity relationship studies of B6B21, a monoclonal antibody that acts as an NMDA receptor partial agonist, with the tetrapeptide sequence derived from the antibody's complementarity-determining region.

Amino Acid Sequence#

The primary structure of rapastinel is remarkably simple: four amino acids with a C-terminal amide.

Thr-Pro-Pro-Thr-NH2

Key structural features:

• Position 1 (Threonine): N-terminal threonine with a free amino group. The hydroxyl side chain may participate in hydrogen bonding with the receptor binding site.
• Positions 2-3 (Proline-Proline): The consecutive proline residues create a rigid turn structure that constrains the peptide backbone into a specific conformation. This rigidity is likely important for receptor binding selectivity.
• Position 4 (Threonine-amide): C-terminal threonine with an amide cap (-NH2) replacing the free carboxylic acid. The amide modification provides resistance to carboxypeptidase degradation.

Pharmacokinetics#

Half-Life and Duration#

The plasma half-life of rapastinel following IV administration is approximately 15-30 minutes. Despite this short half-life, the pharmacodynamic effects persist for approximately 7 days after a single dose, indicating that rapastinel triggers sustained downstream signaling cascades (synaptic plasticity changes) that outlast plasma drug exposure.

Brain Penetration#

Rapastinel crosses the blood-brain barrier following IV administration, confirmed by its central nervous system effects in behavioral studies and clinical trials.

NMDA Receptor Binding#

Rapastinel binds to the NMDA receptor at a site functionally related to but distinct from the canonical glycine co-agonist binding site. At therapeutic concentrations, it functions as a partial agonist, enhancing NMDA receptor-mediated synaptic plasticity.

• vs. Ketamine: Ketamine blocks the NMDA receptor ion channel pore. Rapastinel modulates receptor gating without channel blockade.
• vs. D-cycloserine: Both modulate the glycine site, but rapastinel has a distinct binding profile and pharmacodynamic signature.

Physicochemical Properties#

• Solubility: Freely soluble in aqueous buffers at physiological pH
• Stability: Lyophilized powder stable at -20 degrees C
• Appearance: White to off-white lyophilized powder
• Formulation: Reconstituted in sterile saline for IV infusion

Molecular Context#

Rapastinel belongs to the Neuropeptide category of research peptides. The molecular properties of Rapastinel determine its pharmacological behavior, including receptor binding, distribution, metabolism, and elimination. Understanding these properties is fundamental to interpreting clinical data and designing research protocols.

Structural Overview#

Rapastinel is characterized as: Amidated tetrapeptide with C-terminal amide modification.

Amino Acid Sequence Details#

The amino acid sequence of Rapastinel is: Thr-Pro-Pro-Thr-NH2. This sequence determines the peptide's three-dimensional structure, receptor binding properties, and biological activity.

Pharmacokinetic Profile#

Half-Life: Approximately 15-30 minutes (IV administration)

The half-life of a peptide influences dosing frequency, duration of effect, and the clinical utility of the compound. Researchers should consider the half-life when designing experimental protocols.

Related Reading#

• Rapastinel overview and research guide
• Peptides similar to Rapastinel
• Rapastinel research evidence