Design, synthesis, and biological activity of methoctramine-related polyamines as putative G(i) protein activators.
The universal template approach provided a prospect of modifying methoctramine (2) structure. Thus, polyamines 3-7 were designed in which the flexibility of the diaminohexane spacer of 2 was replaced by a bipiperidinyl moiety. In electrically stimulated guinea pig left atria, these novel polyamines, unlike prototype 2, displayed a potent intrinsic activity, which was in contrast with the muscarinic antagonism shown in binding studies by some of them (3 and 4) and was inhibited by benzalkonium chloride, an inhibitor of G(i) proteins.
Melchiorre
C
C
Department of Pharmaceutical Sciences, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy. camelch@kaiser.alma.unibo.it
Bolognesi
M L
ML
Budriesi
R
R
Ghelardini
C
C
Chiarini
A
A
Minarini
A
A
Rosini
M
M
Tumiatti
V
V
Wade
E J
EJ
D000818:Animals; D016275:Atrial Function; D016466:CHO Cells; D006224:Cricetinae; D003959:Diamines / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D004558:Electric Stimulation; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D018721:Muscarinic Agonists / Q000494:pharmacology; D011073:Polyamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011976:Receptors, Muscarinic / Q000378:metabolism; D013329:Structure-Activity Relationship
D003959:Diamines; D018721:Muscarinic Agonists; D011073:Polyamines; D011976:Receptors, Muscarinic; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; C054938:methoctramine