Conformationally-Restricted analogues and partition coefficients of the 5-HT3 serotonin receptor ligands meta-Chlorophenylbiguanide (mCPBG) and meta-Chlorophenylguanidine (mCPG)

The present investigation examined two features of arylbiguanide and arylguanidine 5-HT3 ligands: conformation and partition coefficients. Several conformationally-constrained analogues of mCPBG (2) and mCPG (11; Ki=32 nM) were prepared and of these only 2-amino-5-chloro-3,4-dihydroquinazoline (14; Ki=34 nM) retained high affinity. The partition coefficient of compound 11 (LogPapp=−0.64) was less than that of its corresponding arylbiguanide 2 (LogPapp=−0.38). The quinazoline structure may represent a pharmacologically-active conformation of these agents, and the arylbiguanides were found more lipid soluble than their arylguanidine counterparts at physiological pH.