The synthesis and oral antihypertensive activity in conscious spontaneously hypertensive rats of two new series of compounds related to the prototype potassium channel activator cromakalim (1) are described. In the first series, replacement of the benzopyran oxygen atom by nitrogen or methylene led to the 1,2,3,4-tetrahydroquinoline 12 and 1,2,3,4-tetrahydronaphthalene 13, which were both less active than 1. However, in contrast to the equivalent activity found previously for 1 and its dehydrated analogue 28, the dihydronaphthalene 27 was found to be more active than 13. In the second series, replacement of the C(4) amide nitrogen atom in acyclic amides related to cromakalim by methylene gave ketone 16 that was less active than the corresponding amide 15. However, replacement of the 4-acetonyl substituent in 16 by N,N-dimethylacetamido as in compound 22 resulted in a marked enhancement in activity. The compounds described in this paper thus illustrate the importance of the benzopyran oxygen and C(4) substituent on antihypertensive activity in the cromakalim series of potassium channel activators.