Starting from two previously studied muscarinic full agonists, characterized by a 1,3-dioxotane ((+)-1) and a 1,3-oxathiolane ((+)-2) cycle. two new series of muscarinic ligands were designed, obtained by the steric complication of the parent compounds produced by freezing the aminoalkyl chain into a pyrrolidine ring. Both tertiary amines and the corresponding iodomethyl derivatives were synthesised and studied, and several compounds of the series which behaved as muscarinic agonists have been selected, on the basis of preliminary binding experiments on rat cortex homogenates, for the present work.Results are presented obtained from testing the affinity of the selected compounds against cloned human muscarinic receptors expressed in CHO cells. in order to evaluate subtype selectivity. Their functional activity on classical models Of M-1-M-4 receptors, in guinea pig and rabbit tissues is also reported.With respect to parent compounds, the new molecules present some selectivity toward hm2 receptors; fair M-2 selectivity is also evident in functional studies, where these compounds behave as partial agonists. Among the other compounds of the series (2S, 4'R, 2'S)-1,1-dimethyl-2-(2-methyl-1,3-dioxolan-4-yl)pyrrolidinium iodide (-)-3 and (2R, 5'S, 2'S)-1-methyl-2-(2-methyl-1,3-oxathiolan-5-yl)pyrrolidine (+)-5 present a promising pharmacological profile. Compound (-)-3 shows modest hm2 selectivity in binding experiments but a clearcut M-2 selectivity in functional tests, where it behaves as a weak antagonist on M-1 and M-4 subtypes, as a weak full agonist on the M-3 subtype and as a potent partial agonist on M-2 Subtype. Tertiary amine (+)-5 presents a quite similar profile but appears more interesting since, lacking a permanent charge on the nitrogen atom, it may represent an interesting tool to study CNS muscarinic receptors.Our results confirm that sterical complication of parent compounds (+)-1 and (+)-2 produces more selective muscarinic agonists. (c) 2005 Elsevier Inc. All rights reserved.
Muscarinic subtype affinity and functional activity profile of 1-methyl-2-(2-methyl-1,3-dioxolan-4-yl)pyrrolidine and 1-methyl-2-(2-methyl-1,3-oxathiolan-5-yl)pyrrolidine derivatives
ANGELI, Piero;BUCCIONI, Michela;MARUCCI, Gabriella;
2005-01-01
Abstract
Starting from two previously studied muscarinic full agonists, characterized by a 1,3-dioxotane ((+)-1) and a 1,3-oxathiolane ((+)-2) cycle. two new series of muscarinic ligands were designed, obtained by the steric complication of the parent compounds produced by freezing the aminoalkyl chain into a pyrrolidine ring. Both tertiary amines and the corresponding iodomethyl derivatives were synthesised and studied, and several compounds of the series which behaved as muscarinic agonists have been selected, on the basis of preliminary binding experiments on rat cortex homogenates, for the present work.Results are presented obtained from testing the affinity of the selected compounds against cloned human muscarinic receptors expressed in CHO cells. in order to evaluate subtype selectivity. Their functional activity on classical models Of M-1-M-4 receptors, in guinea pig and rabbit tissues is also reported.With respect to parent compounds, the new molecules present some selectivity toward hm2 receptors; fair M-2 selectivity is also evident in functional studies, where these compounds behave as partial agonists. Among the other compounds of the series (2S, 4'R, 2'S)-1,1-dimethyl-2-(2-methyl-1,3-dioxolan-4-yl)pyrrolidinium iodide (-)-3 and (2R, 5'S, 2'S)-1-methyl-2-(2-methyl-1,3-oxathiolan-5-yl)pyrrolidine (+)-5 present a promising pharmacological profile. Compound (-)-3 shows modest hm2 selectivity in binding experiments but a clearcut M-2 selectivity in functional tests, where it behaves as a weak antagonist on M-1 and M-4 subtypes, as a weak full agonist on the M-3 subtype and as a potent partial agonist on M-2 Subtype. Tertiary amine (+)-5 presents a quite similar profile but appears more interesting since, lacking a permanent charge on the nitrogen atom, it may represent an interesting tool to study CNS muscarinic receptors.Our results confirm that sterical complication of parent compounds (+)-1 and (+)-2 produces more selective muscarinic agonists. (c) 2005 Elsevier Inc. All rights reserved.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
