Propellanes as Rigid Scaffolds for the Stereodefined Attachment of σ-Pharmacophoric Structural Elements to Achieve σ Affinity

Abstract

Following the concept of conformationally restriction of ligands to achieve high receptor affinity, we exploited the propellane system as rigid scaffold allowing the stereodefined attachment of various substituents. Three types of ligands were designed, synthesized and pharmacologically evaluated as σ₁ receptor ligands. Propellanes with (1) a 2-methoxy-5-methylphenylcarbamate group at the "left" five-membered ring and various amino groups on the "right" side; (2) benzylamino or analogous amino moieties on the "right" side and various substituents at the left five-membered ring and (3) various urea derivatives at one five-membered ring were investigated. The benzylamino substituted carbamate syn,syn-4a showed the highest σ₁ affinity within the group of four stereoisomers emphasizing the importance of the stereochemistry. The cyclohexylmethylamine 18 without further substituents at the propellane scaffold revealed unexpectedly high σ₁ affinity (K_i = 34 nM) confirming the relevance of the bioisosteric replacement of the benzylamino moiety by the cyclohexylmethylamino moiety. Reduction of the distance between the basic amino moiety and the "left" hydrophobic region by incorporation of the amino moiety into the propellane scaffold resulted in azapropellanes with particular high σ₁ affinity. As shown for the propellanamine 18, removal of the carbamate moiety increased the σ₁ affinity of 9a (K_i = 17 nM) considerably. Replacement of the basic amino moiety by H-bond forming urea did not lead to potent σ ligands. According to molecular dynamics simulations, both azapropellanes anti-5 and 9a as well as propellane 18 adopt binding poses at the σ₁ receptor, which result in energetic values correlating well with their different σ₁ affinities. The affinity of the ligands is enthalpy driven. The additional interactions of the carbamate moiety of anti-5 with the σ₁ receptor protein cannot compensate the suboptimal orientations of the rigid propellane and its N-benzyl moiety within the σ₁ receptor-binding pocket, which explains the higher σ₁ affinity of the unsubstituted azapropellane 9a.

Keywords: X-ray crystal structures; azapropellanes; molecular dynamics; molecular interactions; propellanes; rigidity; selectivity; stereochemistry; σ receptors.

Figure 1

Some prototypical σ ligands containing flexible structural elements.

Figure 2

σ Ligands with conformationally restricted spirocyclic (1), bicyclic (2,3) and propellane (4, 5) scaffold.

Figure 3

Designed σ receptor ligands of type A–C. In types A and B, the basic amino moiety is either attached at the cyclopentane ring (m = 1) or incorporated into a ring expanded piperdiene ring (n = 2).

Scheme 1

Synthesis of amino substituted carbamates anti-4 and syn-4. Reagents and reaction conditions: (a) 2-Methoxy-5-methylphenyl isocyanate, Bu₂Sn(OAc)₂, THF, rt, 48 h, 36% (anti-7), 31% (syn-7). (b) RNH₂, NaBH(OAc)₃, HOAc, ClCH₂CH₂Cl, rt, 72 h, 41–93% (exceptions 8-anti-4s (33%)]. 8-anti-4t (21%)). (c) NH₄⁺ HCO₂^-, Pd(OH)₂, CH₃OH, EtOAc, 68%. (d) (Me₂N)C₆H₄CH=O, NaBH(OAc)₃, ClCH₂CH₂Cl, rt, 20 h, 50%. DMABn = (4-dimethylamino)benzyl. The residues R are defined in Table 1.

Figure 4

X-ray crystal structure of carbamate syn-7. Thermal ellipsoids are set at 15% probability. Length of selected bonds: conjoining bond C1–C6 = 1.562(2) Å; C1–C2 = 1.529(2) Å; C1–C7 = 1.528(2) Å; C1–C10 = 1.538(2) Å. CCDC number: 2073466.

Figure 5

Propellan-8-amine 8 [48] and 3-azapropellanes 9 [43] served as lead compounds.

Scheme 2

Synthesis of propellanamines 8 and 13–18. Reagents and reaction conditions: (a) PhCH₂NH₂ (BnNH₂), NaBH(OAc)₃, HOAc, ClCH₂CH₂Cl, rt, 3–8 d, 61–99%; the diastereomeric benzylamines 8-anti-14 and 8-syn-14 were separated by fc; 30% (8-anti-14, 28% (8-syn-14). (b) Tryptamine, NaBH(OAc)₃, HOAc, ClCH₂CH₂Cl, rt, 5 d, rt, 33%. (c) NH₄⁺ HCO₂^-, Pd(OH)₂, CH₃OH, 65 °C, 3 h, 75%. (d) (Me₂N)C₆H₄CH=O or cyclohexanecarbaldehyde, NaBH(OAc)₃, ClCH₂CH₂Cl, rt, 72 h 98% (17) or 12 h, 91% (18).

Scheme 3

Synthesis of N-benzylurea derivatives 21 and 22. Reagents and reaction conditions: (a) C₆H₅CH₂NH₂ (BnNH₂), NaBH(OAc)₃, HOAc, ClCH₂CH₂Cl, rt, 96 h, 16% (syn-20), 9% (anti-20). (b) 2-Methoxy-5-methylphenyl isocyanate, Bu₂Sn(OAc)₂, THF, rt, 18 h, 70% (syn-21), 82% (anti-21). (c) NaBH₄, CH₃OH, THF, rt, 30 min, 43% (syn,anti-22), (syn,syn-22), 33% (anti,anti-22) and 38% (anti,syn-22).

Figure 6

X-ray crystal structure of N-benzylurea anti-21. Thermal ellipsoids are set at 15% probability. Length of selected bonds: conjoining bond C1–C6 = 1.550(3) Å; C1–C2 = 1.523(4) Å; C1–C9 = 1.530(3) Å; C1–C12 = 1.548(4) Å. CCDC number: 2073467.

Figure 7

X-ray crystal structure of N-benzyl urea syn,anti-22. Thermal ellipsoids are set at 15% probability. Selected bond lengths: C1–C6 = 1.559(2) Å; C1–C2 = 1.535(2) Å; C1–C9 = 1.529(2) Å; C1–C12 = 1.552(2) Å. CCDC number: 2073468.

Figure 8

X-ray crystal structure of N-benzyl urea anti,syn-22. Thermal ellipsoids are set at 15% probability. Selected bond lengths: C1–C6 = 1.590(2) Å; C1–C2 = 1.535(3) Å; C1–C9 = 1.538(2) Å; C1–C12 = 1.544(2) Å. CCDC number: 2073469.

Scheme 4

Synthesis of propellane-based urea derivatives 23. Reagents and reaction conditions: (a) R-N=C=O, Bu₂Sn(OAc)₂, THF, rt, 24–48 h, 22–91%. Since a 1:1-mixture of diastereomeric primary amines 16 was used as starting material, 1:1-mixtures of urea 23 were obtained. The residues R are defined in Table 3.

Scheme 5

Synthesis of diastereomeric difluorophenyl substituted urea derivatives. Reagents and reaction conditions: (a) NH₄⁺ HCO₂⁻, Pd(OH)₂, CH₃OH, 65 °C, 3 h, 75%. (b) 3,4-Difluorophenyl isocyanate, Bu₂Sn(OAc)₂, THF, rt, 48 h. (c) pTsOH^.H₂O, acetone, 60 °C, 2 h, 42%, (syn-25) and 35% (anti-25). (d) NaBH₄, CH₃OH, THF, rt, 30 min, 83% (1:1 mixture of (syn,anti-26) and (syn,syn-26); 27% (anti,anti-26) and 8% (anti,syn-26).

Figure 9

X-ray crystal structure of unsubstituted urea syn-25. Thermal ellipsoids are set at 15% probability. Selected bond lengths: C1–C6 = 1.546(3) Å; C1–C2 = 1.529(4) Å; C1–C9 = 1.548(4) Å; C1–C10 = 1.517(3) Å. CCDC number: 2073470. Only one molecule (molecule A) of three independent molecules found in the asymmetric unit is discussed.

Figure 10

Details of an equilibrated MD snapshot of 9a (A) and anti-5 (B) in the binding pocket of σ₁ receptor. The compounds are shown as atom-colored sticks-and-balls (C, grey, N, blue and O, red) while the side chains of σ₁ residues mainly interacting with the ligands are depicted as colored sticks and labeled. Hydrogen atoms, water molecules, ions, and counterions are omitted for clarity. 2D schematic representation of the general stabilizing interactions for σ₁/9a (C) and σ₁/anti-5 (D) complexes. (E) Per-residue binding free energy decomposition (ΔH_res) of the main involved amino acids in σ₁/9a (light sea green) and σ₁/anti-5 (firebrick) complexes. (F) MD distance between the carboxyl oxygen atom (O2) of E172 and the NH group of the ligand detected for σ₁/9a (light sea green) and σ₁/anti-5 (firebrick) complexes. (G) MD distance between the OH group of Y103 and the carboxyl oxygen atom (O1) of E172 detected for σ₁/9a (light sea green) and σ₁/anti-5 (firebrick) complexes.