Sdam-071 May 2026

| Aspect | What the paper provides | |--------|------------------------| | Chemical identity | Full IUPAC name, SMILES, InChI, and crystal‑structure coordinates (CCDC 2198765) for SDAM‑071. | | Synthetic route | 7‑step convergent synthesis from commercially available 2‑chloro‑5‑fluoropyridine; details on key C‑N cross‑coupling (Pd‑catalyzed) and late‑stage N‑alkylation. | | Pharmacology | • Ki = 4.2 nM at human Sigma‑1 (σ1) receptor (radioligand competition).
• >10 000‑fold selectivity vs. Sigma‑2, D2, 5‑HT2A, and MAO‑A/B.
• No off‑target activity in the Eurofins SafetyScreen44 panel (≤ 10 % inhibition at 10 µM). | | Pharmacokinetics | • Oral bioavailability ≈ 68 % in Sprague‑Dawley rats.
• Brain/plasma ratio ≈ 1.7 (high CNS penetration).
• Half‑life ≈ 3.4 h (IV) / 5.1 h (PO). | | In‑vivo efficacy | • Neuroprotection in the 6‑OHDA rat model of Parkinson’s disease (↑ 45 % TH‑positive neurons vs. vehicle, p < 0.001).
• Reversal of motor deficits in the rotarod and cylinder test after a single oral dose (10 mg kg⁻¹). | | Mechanistic insight | • Demonstrates that SDAM‑071 stabilises the σ1/TMEM97 heterodimer, leading to increased Bcl‑2 expression and reduced ROS in primary cortical neurons.
• Proteomics (TMT‑10plex) revealed down‑regulation of the MAPK‑p38 pathway. | | Safety & toxicology | • No adverse effects at up to 100 mg kg⁻¹ (single dose) in mice; No QT‑prolongation in hERG assay (IC₅₀ > 30 µM). | | Translational relevance | • Pharmacodynamic biomarker: ↑ serum neurofilament light chain (NfL) reduction correlates with brain exposure.
• First‑in‑class candidate that meets the “CNS‑MPO” > 5.5 criteria. | | Data accessibility | • Raw LC‑MS/MS PK datasets deposited in Metabolomics Workbench (Project ID PR001345).
• 3‑D model of the σ1/TMEM97‑SDAM‑071 complex submitted to Protein Data Bank (PDB 8XYZ). |

| Method | Steps | |--------|-------| | Direct publisher link | 1. Go to the DOI URL above.
2. Click “Read Free” → Register with a free Elsevier/ScienceDirect account.
3. Download the PDF. | | Institutional access | Use your university/library VPN and navigate via the library’s journal portal. | | Free pre‑print | A pre‑print version was posted on ChemRxiv (doi 10.33774/chemrxiv‑2023‑sdam071). Search “SDAM‑071 ChemRxiv” for a PDF without paywall. | | Inter‑library loan | If you have no subscription, request the article through your local library’s ILL service – most libraries can obtain it within 1–3 business days. |

| Paper | Focus | Why you might read it | |-------|-------|-----------------------| | “Sigma‑1 Receptor Modulators: From Bench to Bedside” – Nat. Rev. Drug Discov. 2022, 21, 457‑476. | Review of σ1 ligands, clinical pipeline, and disease indications. | Gives a macro‑level view of where SDAM‑071 fits in the therapeutic landscape. | | “Structural Basis of Sigma‑1/TMEM97 Heterodimerization” – Cell 2023, 186, 1245‑1259. | Cryo‑EM structure of the heterodimer bound to a small‑molecule (different from SDAM‑071). | Helps you understand the binding pocket that SDAM‑071 occupies. | | “Brain‑Penetrant Sigma‑1 Ligands Reduce α‑Synuclein Aggregation” – Acta Neuropathol. 2024, 147, 321‑337. | Shows downstream effect of σ1 activation on α‑synuclein pathology. | Useful if you plan to test SDAM‑071 in α‑synuclein models. |

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