The pentafluorosulfanyl group in cannabinoid receptor ligands: synthesis and comparison with trifluoromethyl and tert-butyl analogues

An array of cannabinoid ligands, bearing meta-and para-substituted pentafluorosulfanyl (SF5) aniline groups in position 3 of the pyrazole ring, was efficiently synthesised and compared with the exact trifluoromethyl and tert-butyl analogues. In general, the SF5 substituted ligands showed higher lipophilicity (i.e. log P values) than the CF3 counterparts and lower lipophilicity than the tert-butyl ones. In terms of pharmacological activity, SF5 pyrazoles generally showed slightly higher or equivalent CB1 receptor affinity (K-i), always in the nanomolar range, and selectivity towards the CB2 relative to both CF3 and tert-butyl analogues. Functional beta-arrestin recruitment assays were used to determine equilibrium dissociation constants (K-b) and showed that all of the tested SF5 and CF3 compounds are CB1 neutral antagonists. These results confirm the possibility of successfully using an aromatic SF5 group as a stable, synthetically accessible and effective bioisosteric analogue of the electron-withdrawing CF3 group, and possibly also of bulky aliphatic groups, for drug discovery and development applications.