An array of cannabinoid ligands, bearing
meta- and
para-substituted pentafluorosulfanyl (SF
5) 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 SF
5 substituted ligands showed higher lipophilicity (
i.e. log
P values) than the CF
3 counterparts and lower lipophilicity than the
tert-butyl ones. In terms of pharmacological activity, SF
5 pyrazoles generally showed slightly higher or equivalent CB
1 receptor affinity (
Ki), always in the nanomolar range, and selectivity towards the CB
2 relative to both CF
3 and
tert-butyl analogues. Functional β-arrestin recruitment assays were used to determine equilibrium dissociation constants (
Kb) and showed that all of the tested SF
5 and CF
3 compounds are CB
1 neutral antagonists. These results confirm the possibility of successfully using an aromatic SF
5 group as a stable, synthetically accessible and effective bioisosteric analogue of the electron-withdrawing CF
3 group, and possibly also of bulky aliphatic groups, for drug discovery and development applications.