TACR1

TACR1 encodes the NK1 receptor - the class A GPCR for substance P (SP), the 11-aa tachykinin neuropeptide that drives pain transmission, neurogenic inflammation, emesis, and anxiety circuitry. NK1 antagonists are FDA-approved as antiemetics for chemotherapy-induced nausea and vomiting (CINV): aprepitant was the first in 2003, and elinzanetant (NK1/NK3 dual antagonist) was approved in October 2025 for menopausal vasomotor symptoms. Despite SP's role in pain sensitization, NK1 antagonists have failed in clinical pain trials - a cautionary translational data point for this scaffold. The SP/NK1 axis remains active for CINV, PONV, pruritis, and the newly validated vasomotor symptom indication.

TACR1 (chromosome 2p12, 407 aa) is a Gq/11-primary class A GPCR. Substance P (Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH₂) is the highest-affinity endogenous agonist (Ki ~0.1 nM); the C-terminal Phe⁷-Met¹¹ pentapeptide is the minimal pharmacophore (Phe-X-Gly-Leu-Met-NH₂). Neurokinin A binds NK1 with ~10-fold lower affinity; neurokinin B binds at ~1000-fold lower affinity. Crystal structure (PDB: 6J20, inactive with aprepitant) revealed a deep narrow binding pocket lined by aromatic TM3/TM5/TM6/TM7 residues; active cryo-EM structures (PDB: 7RMH, with Gq and SP) show TM6 outward displacement and SP N-terminal residues engaging a polar extracellular network. Signaling: Gq/11 → PLC-β → IP3/Ca²⁺/PKC → MAPK/ERK; Gs → cAMP; Gi/o and Gα12/13 contribute in some cell contexts. β-arrestin drives receptor internalization and endosomal ERK. Dense TACR1 expression in area postrema and nucleus tractus solitarius (emesis), dorsal root ganglia and spinal dorsal horn (pain), amygdala and limbic circuits (anxiety, depression), and skin/vascular endothelium (neurogenic inflammation). Species-specific difference: aprepitant binds human NK1 with IC₅₀ ~0.1 nM but rat NK1 10–100-fold weaker - ferret/gerbil models were required for preclinical development.

Approved NK1 antagonists: aprepitant (oral, CINV/PONV), fosaprepitant (IV prodrug, CINV), netupitant (combined with palonosetron as NEPA/Akynzeo for CINV), rolapitant (oral, single-dose, CINV), elinzanetant (NK1/NK3 dual, oral, menopausal vasomotor symptoms - October 2025). For peptide research, the tractable recipes are: SP C-terminal pentapeptide (Phe-Phe-Gly-Leu-Met-NH₂) constrained with N-methylation or lactam bridges for in vitro NK1 binding probes resistant to neutral endopeptidase; full-length SP analogs with [Sar⁹,Met(O₂)¹¹]-SP pharmacophore modifications for protease-stable agonist tools in neuroinflammation models; endosome-targeted lipophilic SP antagonist conjugates (based on sustained-acting antagonist discoveries showing endosomal NK1 drives persistent pain signaling) that achieve intracellular receptor blockade; and NK1/NK3 dual-peptide ligands incorporating the SP C-terminus and NKB N-terminus in a single bifunctional scaffold for vasomotor symptom applications informed by elinzanetant's clinical validation.