5-FEAI

Dual TAAR1 agonist / DAT inhibitor ADHD · pro‑cognitive

5‑Fluoro‑N‑ethyl‑2‑aminoindane

Molecular weight

179.23 g/mol

C₁₁H₁₄FN

cLogP

2.14

Optimal CNS penetration

Predicted half‑life

6.5–8.0 h

Fluorine metabolic shield

How it works · two‑pronged precision

TAAR1

EC₅₀ 28.4 nM

95% efficacy · cAMP ↑

DAT

Kᵢ 142 nM

reuptake inhibitor

ρ = [L] / ([L] + K_d) · K_i = IC₅₀ / (1 + [DA]/K_m) occupancy & Cheng‑Prusoff

Target engagement

Minimal serotonergic & direct D₂ engagement → low off‑target

TAAR1–D₂R heteromer

Functional heteromers in mesocorticolimbic regions — 5‑FEAI triggers β‑arrestin‑2 and GSK3β inactivation.

d[cAMP]/dt =

k_syn · (τ·[A]/(K_A + (1+τ)[A]))
− k_inhib · ([DA]/(K_d,D2+[DA]))
− k_deg·[cAMP]

GSK3β → pGSK3β (inactive)

Dampens dopaminergic hyper‑responsiveness

SAR · metabolic shielding

Rigid indane core – locks dihedral θ ≈ 0–30°, boosts TAAR1 selectivity, avoids 5‑HT₂A

5‑Fluoro – blocks CYP2D6 hydroxylation, extends t₁/₂ (CL_hepatic ↓)

N‑ethyl – steric hindrance stops MAO‑B recognition

2‑aminoindane · 5‑F · N‑ethyl

t_1/2 = (ln2 · V_d) / (CL_hepatic + CL_renal) → fluorine reduces CL_hepatic → predicted 6.5–8 h

Next‑generation D₂‑focused analogues

Compound	Target profile	t_1/2	D₂ efficacy	Advantage / risk
5‑FEAI (lead)	TAAR1 full / DAT inhibitor	7.0 h	12% (indirect)	Low abuse liability; moderate direct D₂
5‑OH‑6‑F‑PAT Class A	TAAR1 partial / D₂ partial agonist	4.5 h	28% (direct)	Superior executive enhancement; potential O‑methylation
IPC‑04 Class B	TAAR1–D₂R bivalent modulator	11.5 h	18% (biased)	High circuit specificity; MW > 380

Class A: tetralin‑amine hybrids

6‑F‑2‑(N‑propylamino)‑tetralin‑5‑ol · D₂ partial (ε≈0.25) → autoreceptor stabilization, low abuse

Class B: bivalent chimera

Indane‑piperazine tether (IPC‑04) · K_bivalent = K_d1·K_d2/C_eff → orders‑of‑magnitude selectivity for heteromers

5‑FEAI: dual‑action, low abuse potential, pro‑cognitive candidate for ADHD

TAAR1 full agonist DAT inhibitor