A structure−activity relationship (SAR) study was performed principally at the N¹ position of N¹-arylsulfonyl-N²-[1-(1-naphthyl)ethyl]-trans-1,2-diaminocyclohexanes, a new family of calcilytics acting at the calcium sensing receptor (CaSR). The most active compound in this series was the 4-(trifluoromethoxy)benzenesulfonyl derivative 7e, which displayed an IC₅₀ of 5.4 ± 0.5 μM with respect to the inhibition of calcium-induced tritiated inositol phosphate ([³H]IP) accumulation in Chinese hamster ovarian (CHO) cells expressing the CaSR. Replacement of the sulfonamide linkage of this compound by a carboxamide led to a 6-fold increase in activity (7m, IC₅₀ = 0.9 ± 0.2 μM). Among the carboxamides synthesized, one of the most active compounds was the 4-chlorophenylcarboxamide (1S,2S,1‘R)-7n (Calhex 231, IC₅₀ = 0.33 ± 0.02 μM). The absolute configuration of (1S,2S,1‘R)-7n was deduced from an X-ray crystallographic study of one of the diastereomers of compound 7d. The stereochemical preference for the (1S,2S,1‘R)-isomers can be rationalized on the basis of a three-dimensional model of the calcilytic binding pocket of the CaSR. Removal of the C-1‘ methyl group or replacement of the 1-naphthyl group by a 2-naphthyl or biphenyl moiety led to appreciable loss of calcilytic activity. Compounds 7e, 7m, and Calhex 231 did not stimulate [³H]IP accumulation in CHO cells expressing or not expressing the CaSR.