Conformationally-restricted analogues and partition coefficients of the 5-HT3 serotonin receptor ligands meta-chlorophenylbiguanide (mCPBG) and meta-chlorophenylguanidine (mCPG)

  • Bioorg Med Chem Lett. 2003 Mar 24;13(6):1119-23. doi: 10.1016/s0960-894x(03)00044-1.
Ashraf A Rahman  1 ,  Maha Khalifa Daoud ,  Małgorzata Dukat ,  Katharine Herrick-Davis ,  Anil Purohit ,  Milt Teitler ,  Antonia Taveres do Amaral ,  Alberto Malvezzi ,  Richard A Glennon
Affiliations
  • 1. Department of Medicinal Chemistry, School of Pharmacy, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298-0540, USA.
PMID: 12643925 DOI: 10.1016/s0960-894x(03)00044-1
Abstract

The present investigation examined two features of arylbiguanide and arylguanidine 5-HT(3) ligands: conformation and partition coefficients. Several conformationally-constrained analogues of mCPBG (2) and mCPG (11; K(i)=32 nM) were prepared and of these only 2-amino-5-chloro-3,4-dihydroquinazoline (14; K(i)=34 nM) retained high affinity. The partition coefficient of compound 11 (LogP(app)=-0.64) was less than that of its corresponding arylbiguanide 2 (LogP(app)=-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.

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