Synthesis and serotonergic activity of substituted 2, N-benzylcarboxamido-5-(2-ethyl-1-dioxoimidazolidinyl)-N, N-dimethyltryptamine derivatives: novel antagonists for the vascular 5-HT(1B)-like receptor.
The synthesis and vascular 5-HT(1B)-like receptor activity of a novel series of substituted 2, N-benzylcarboxamido-5-(2-ethyl-1-dioxoimidazolidinyl)-N, N-dimethyltryptamine derivatives are described. Modifications to the 5-ethylene-linked heterocycle and to substituents on the 2-benzylamide side chain have been explored. Several compounds were identified which exhibited affinity at the vascular 5-HT(1B)-like receptor of pK(B) > 7.0, up to 100-fold selectivity over alpha(1)-adrenoceptor affinity and 5-HT(2A) receptor affinity, and which exhibited a favorable pharmacokinetic profile. N-Benzyl-3-[2-(dimethylamino)ethyl]-5-[2-(4,4-dimethyl-2, 5-dioxo-1-imidazolidinyl)ethyl]-1H-indole-2-carboxamide (23) was identified as a highly potent, silent (as judged by the inability of angiotensin II to unmask 5-HT(1B)-like receptor-mediated agonist activity in the rabbit femoral artery), and competitive vascular 5-HT(1B)-like receptor antagonist with a plasma elimination half-life of approximately 4 h in dog plasma and with good oral bioavailability. The selectivity of compounds from this series for the vascular 5-HT(1B)-like receptors over other receptor subtypes is discussed as well as a proposed mode of binding to the receptor pharmacophore. It has been proposed that the aromatic ring of the 2, N-benzylcarboxamide group can occupy an aromatic binding site rather than the indole ring. The resulting conformation allows an amine-binding site to be occupied by the ethylamine nitrogen and a hydrogen-bonding site to be occupied by one of the hydantoin carbonyls. The electronic nature of the 2,N-benzylcarboxamide aromatic group as well as the size of substituents on this aromatic group is crucial for producing potent and selective antagonists. The structural requirement on the 3-ethylamine side chain incorporating the protonatable nitrogen is achieved by the bulky 2, N-benzylcarboxamide group and its close proximity to the 3-side chain.
Department of Medicinal Chemistry, Victorian College of Pharmacy, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia. Gerard.Moloney@vcp.monash.edu.au
G P
GP
Moloney
G R
GR
Martin
N
N
Mathews
A
A
Milne
H
H
Hobbs
S
S
Dodsworth
P Y
PY
Sang
C
C
Knight
M
M
Williams
M
M
Maxwell
R C
RC
Glen
D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000378:metabolism; D004285:Dogs; D005263:Femoral Artery / Q000378:metabolism; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D008958:Models, Molecular; D009130:Muscle, Smooth / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000187:drug effects*; D012501:Saphenous Vein / Q000378:metabolism; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D014132:Trachea / Q000378:metabolism
D007093:Imidazoles; D007211:Indoles; C120303:N-benzyl-3-(2-(dimethylamino)ethyl)-5-(2-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)ethyl)-1H-indole-2-carboxamide; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists