title: Conformationally-restricted analogues and partition coefficients of the 5-HT3 serotonin receptor ligands meta-chlorophenylbiguanide (mCPBG) and meta-chlorophenylguanidine (mCPG).
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.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298-0540, USA.
authors.forename: Ashraf A
authors.initials: AA
authors.lastname: Rahman
authors.forename: Maha Khalifa
authors.initials: MK
authors.lastname: Daoud
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Dukat
authors.forename: Katharine
authors.initials: K
authors.lastname: Herrick-Davis
authors.forename: Anil
authors.initials: A
authors.lastname: Purohit
authors.forename: Milt
authors.initials: M
authors.lastname: Teitler
authors.forename: Antonia Taveres
authors.initials: AT
authors.lastname: do Amaral
authors.forename: Alberto
authors.initials: A
authors.lastname: Malvezzi
authors.forename: Richard A
authors.initials: RA
authors.lastname: Glennon
mesh_terms: 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
chemical_list: D001645:Biguanides; D008024:Ligands; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; C478080:chlorophenylguanidine; C065734:1-(3-chlorophenyl)biguanide; D019791:Guanidine