The agonist properties of m-chlorophenylbiguanide and 2-methyl-5-hydroxytryptamine on 5-HT3 receptors in N1E-115 neuroblastoma cells.

1. The effects of 5-HT3 selective agonists have been studied in whole-cell voltage-clamped N1E-115 neuroblastoma cells. 2. Application of 5-hydroxytryptamine (5-HT) results in the rapid development of a transient inward current at quasiphysiological membrane potentials. This current can be blocked by the 5-HT3 specific antagonists BRL 43694 and GR67330. 3. Application of 2-methyl-5-HT (2-Me5-HT), a 5-HT3 selective agonist, produced a qualitatively similar inward current, but with a maximum response only 20% of that produced by 5-HT. 4. In the presence of 100 microM 2-Me5-HT, the upper part of the 5-HT dose-response curve was shifted to the right but reached the same maximum value as in the absence of 2-Me5-HT. 2-Me5-HT appears therefore to be a partial agonist under these conditions. 5. The novel 5-HT3 agonist, meta-chlorophenylbiguanide (mCPBG) is a full agonist, but has a Hill coefficient (1.5) significantly less than that of 5-HT (2.3). 6. Comparison with radioligand binding data show that mCBPG is 100 times less potent than expected; it may therefore exhibit a high affinity for a desensitized state.