Histamine H3 receptor ligands with a 3-cyclobutoxy motif: a novel and versatile constraint of the classical 3-propoxy linkerElectronic supplementary information (ESI) available: Gradient programs, compound purities, pharmacological procedures, computational studies, synthetic procedures and NMR spectra. See DOI: 10.1039/c0md00056f

Antagonists/inverse agonists for the histamine H 3 receptor (H 3 R) are subject to intensive research. Many chemical classes contain a 3-propoxy linker to connect an aromatic moiety and a basic amine. Rigidifying this linker by several moieties has proven successful. However, so far, a 3-cyclobutoxy constraint has not been disclosed in H 3 R research. Here, we present novel synthetic methodology toward compounds with this functionality. A condensation between piperidine and 1,3-cyclobutanedione followed by a reduction furnishes a versatile cis -3-piperidino-cyclobutanol building block which allows ready access to constrained compounds having a 3-piperidino-cyclobutoxy moiety. Pharmacological studies reveal that this particular rigidification leads to a significant increase in H 3 R affinity compared to the non-constrained counterpart. In all, the constrained 3-cyclobutoxy linker emerges as a novel, versatile and attractive motif for H 3 R ligands. Constraining the classical 3-propoxy linker to a 3-cyclobutoxy moiety reveals a versatile and attractive motif for histamine H 3 R ligands.