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1Isopolar methylene phosphonate analogues ofadenosine triphosphate (ATP) were synthesized and tested on the guinea-pig isolated taenia coli (where ATP causes relaxation) and urinary bladder (where ATP causes contraction), to see if restoration of the electronegativity of the methylene linkage would enhance pharmacological potency. The compounds used were the dichloromethylene and difluoromethylene analogues of adenosine 5'-(P,y-methylene)triphosphonate (AMP-PCP), L-adenosine 5'-(P,y-methylene)triphosphonate (L-AMP-PCP) and 2-methylthioadenosine 5'-(f,y-methylene)-triphosphonate (2-methylthio-AMP-PCP). 2 The order ofpotency of the analogues depended on the tissue, and was independent of the nature of the purine or ribose moieties. None of the analogues was degraded by ectonucleotidases on either tissue. 3 In the taenia coli the order of potency for relaxation was difluoromethylene > dichloromethylene > methylene, and this reflected the order ofelectronegativity of the analogues. The isopolar analogues of L-AMP-PCP were inactive in the taenia coli. 4 In the bladder the order of potency for contraction was difluoromethylene> methylene> dichloromethylene, suggesting that electronegativity is of lesser importance here. The isopolar analogues of L-AMP-PCP were active in this tissue. 5 The differences between the two tissues in the order of potency for these non-degradable analogues supports suggestions that P2-purinoceptors in the taenia coli (P2y) are different from those in the bladder (P2X). The isopolar analogues of L-AMP-PCP, like L-AMP-PCP itself, were selective agonists at the P2x-purinoceptor.