ABSTRACT
A series of N-[(3S)-1-benzylpyrrolidin-3-yl]-(2-thienyl)benzamides 8 has been prepared and found to bind with high affinity to the human D(4) (hD(4)) and 5-HT(2A) receptors. Several compounds displayed selectivity for these receptors versus hD(2) and alpha(1) adrenergic receptors of over 500-fold.
Subject(s)
Antipsychotic Agents/chemistry , Antipsychotic Agents/pharmacology , Benzamides/chemistry , Benzamides/pharmacology , Receptors, Dopamine D4/antagonists & inhibitors , Serotonin 5-HT2 Receptor Antagonists , Antipsychotic Agents/chemical synthesis , Benzamides/chemical synthesis , Dopamine/chemistry , Humans , LigandsABSTRACT
A series of N-(1-benzylpyrrolidin-3-yl)arylbenzamides 8 has been prepared, and their structure-activity relationships studied. Potent ligands selective for human D(4) (hD(4)) over hD(2) and alpha(1) have been identified. One example was determined to be an antagonist in a cAMP assay, with an IC(50) of 1500 nM.
Subject(s)
Benzamides/chemical synthesis , Dopamine Antagonists/chemical synthesis , Dopamine D2 Receptor Antagonists , Benzamides/pharmacology , Dopamine Antagonists/pharmacology , Humans , Receptors, Dopamine D4 , Structure-Activity RelationshipABSTRACT
A series of 3-(2-pyrrolidin-1-ylethyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives (2) has been prepared using parallel synthesis techniques, and their structure-activity relationships studied. High affinity human 5-HT(1B/1D) (h5-HT(1B/1D)) ligands have been identified.
Subject(s)
Indoles/chemistry , Indoles/metabolism , Pyridines/chemistry , Pyridines/metabolism , Receptor, Serotonin, 5-HT1B/metabolism , Humans , Ligands , Structure-Activity RelationshipABSTRACT
A series of (R)-3-(N-methylpyrrolidin-2-ylmethyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives (2) have been prepared using parallel synthesis, and their structure-activity relationship studied. High affinity human 5-HT(1B/1D) (h5-HT(1B/1D)) ligands have been identified.
Subject(s)
Pyridines/chemistry , Receptor, Serotonin, 5-HT1B/metabolism , Receptor, Serotonin, 5-HT1D/metabolism , Humans , Ligands , Pyridines/chemical synthesis , Pyridines/metabolism , Structure-Activity RelationshipABSTRACT
Reaction of the 1,2-bisketene (Me(3)SiC=C=O)(2) (1) with alcohols (ROH) catalyzed by LiOR gives rapid and efficient conversion to mixtures of the meso and dl succinates (Me(3)SiCHCO(2)R)(2) (4). There is a change in selectivity with the dl/meso ratio varying from 18/82 with MeOH to 92/8 for t-BuOH. This procedure occurs with minimal desilylation, which is the predominant path in the uncatalyzed reaction. Preferential attack of lithium alkoxides on the carbonyl carbon of ketenes induced by lithium coordination to the ketenyl oxygen is proposed to account for the low extent of desilylation. The stereochemical assignments of the meso and dl configurations are based upon vicinal H,H coupling constants both from a mixed succinate ester and also from (13)C,(1)H satellite spectra and are confirmed by X-ray structure determinations. Reaction of 1 with catechols 10-12 catalyzed by n-BuLi leads to ortho esters 15-18, while reaction with the perhalo catechols 13 and 14 gives isolable hydroxaryl ketenyl esters 19 and 20.
