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-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.
Rahman
Ashraf A
AA
Department of Medicinal Chemistry, School of Pharmacy, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298-0540, USA.
Daoud
Maha Khalifa
MK
Dukat
Małgorzata
M
Herrick-Davis
Katharine
K
Purohit
Anil
A
Teitler
Milt
M
do Amaral
Antonia Taveres
AT
Malvezzi
Alberto
A
Glennon
Richard A
RA
D001645:Biguanides / Q000138:chemical synthesis* / Q000494:pharmacology*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D019791:Guanidine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D011869:Radioligand Assay; D011985:Receptors, Serotonin / Q000187:drug effects*; D044406:Receptors, Serotonin, 5-HT3; D012995:Solubility; D013329:Structure-Activity Relationship
D001645:Biguanides; D008024:Ligands; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; C478080:chlorophenylguanidine; C065734:1-(3-chlorophenyl)biguanide; D019791:Guanidine