title: Synthesis and evaluation of analogues of the partial agonist 6-(propyloxy)-4-(methoxymethyl)-beta-carboline-3-carboxylic acid ethyl ester (6-PBC) and the full agonist 6-(benzyloxy)-4-(methoxymethyl)-beta-carboline-3-carboxylic acid ethyl ester (Zk 93423) at wild type and recombinant GABAA receptors.
abstract: A pharmacophore and an alignment rule have previously been reported for BzR agonist ligands. The design and synthesis of 6-(propyloxy)-4-(methoxymethyl)-beta-carboline-3-carboxylic acid ethyl ester (6-PBC, 24, IC50 = 8.1 nM) was based on this pharmacophore. When evaluated in vivo this ligand exhibited anticonvulsant/anxiolytic activity but was devoid of the muscle relaxant/ataxic effects of "classical" 1,4-benzodiazepines (i.e., diazepam). Significantly, 6-PBC 24 also reversed diazepam-induced muscle relaxation in mice. The 3-substituted analogues 40-46 and 48 of 6-PBC 24 and Zk 93423 27(IC50 = 1 nM) were synthesized and evaluated in vitro to determine what affect these modifications would have on the binding affinity at recombinant BzR subtypes. With the exception of the 3-amino ligands 40 and 41, all the beta-carbolines were found to exhibit high binding affinity at BzR sites. The 3-propyl ether derivative 45 was also evaluated in vivo and found to be devoid of any proconvulsant or anticonvulsant activity at doses up to 40 mg/kg. The 6-(1-naphthylmethyloxy) and 6-octyloxy analogues 25, 26, 28, and 29 of 6-PBC 24 were synthesized to further evaluate the proposed alignment of agonists vs inverse agonists in the pharmacophore of the BzR. In addition, ligands 26 and 29 were designed to probe the dimensions of lipophilic pocket L3 at the agonist site. The activity of 29 was evaluated in vivo; however, this analogue elicited no pharmacological effects at doses up to 80 mg/kg. These and other related beta-carbolines were also examined in five recombinant GABAA receptor subtypes. Ligands 52-61 all exhibited moderate to high affinity at GABAA receptors containing alpha1 subunits. These ligands will be useful in further defining the pharmacophore at alpha1 beta3 gamma2 receptors.
authors.affiliation: Department of Chemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53201, USA.
authors.forename: E D
authors.initials: ED
authors.lastname: Cox
authors.forename: H
authors.initials: H
authors.lastname: Diaz-Arauzo
authors.forename: Q
authors.initials: Q
authors.lastname: Huang
authors.forename: M S
authors.initials: MS
authors.lastname: Reddy
authors.forename: C
authors.initials: C
authors.lastname: Ma
authors.forename: B
authors.initials: B
authors.lastname: Harris
authors.forename: R
authors.initials: R
authors.lastname: McKernan
authors.forename: P
authors.initials: P
authors.lastname: Skolnick
authors.forename: J M
authors.initials: JM
authors.lastname: Cook
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D002243:Carbolines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D015195:Drug Design; D018755:GABA Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D009126:Muscle Relaxation / Q000187:drug effects; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012640:Seizures / Q000503:physiopathology / Q000517:prevention & control; D013329:Structure-Activity Relationship
chemical_list: D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D002243:Carbolines; D018755:GABA Agonists; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; C068884:6-propoxy-4-(methoxymethyl)-beta-carboline-3-carboxylic acid ethyl ester; C042569:ZK 93423