Synthesis and benzodiazepine receptor affinities of rigid analogs of 3-carboxy-.beta.-carbolines: demonstration that the benzodiazepine receptor recognizes preferentially the s-cis conformation of the 3-carboxy group

Abstract

1H-Indolo[3',2':4,5]pyrido[3,2-b]-2-penten-5-olide (6) and 1H,5H-indolo[3',2'-c]-6,7-dihydro-2-pyridone (7), rigid analogues of methyl 4-ethyl-beta-carboline-3-carboxylate (8) and N-methyl-4-ethyl-beta-carboline-3-carboxamide (9), respectively, were synthesized and their in vitro binding affinities to the central type benzodiazepine receptors were compared. The IC50 values of 6 and 8 were approximately equivalent (42 and 27 nM, respectively). The amide derivative 9, for which theoretical energy calculations indicate that the s-trans carbonyl conformation is the preferred one, displayed very low affinity (IC50 greater than 10(4) nM). However, when the carbonyl group of 9 was forced to adopt the s-cis conformation as in lactam 7, binding to the benzodiazepine receptor was largely restored (IC50 = 150 nM), indicating that the s-cis carboxy conformation at C-3 of beta-carbolines is preferentially recognized by this receptor. In vivo, compound 6 showed neither convulsant, proconvulsant, nor anticonvulsant activity in mice. Moreover, 6 did not antagonize methyl beta-carboline-3-carboxylate induced convulsions in mice. This lack of activity of 6 was attributed to its inability to cross the blood-brain barrier since no significant displacement of [3H]Ro 15-1788 from mouse brain benzodiazepine receptors by 6 could be observed in vivo.

Structural features controlling the binding of β-carbolines to the benzodiazepine receptor

“…All the carbolines tested are characterized by an ester function in position 3. The conformation with the carbonyl syn with respect to N1 has been chosen because it is systematically more stable by 8± 12 kJ mol À1 in agreement with the great majority of crystal structures so far determined (the only exception being DMCM: Bertolasi et al, 1990) and because it is generally believed to be the active conformation in drug binding (Dorey et al, 1989).…”

Synthesis of Tetracyclic Tetrahydro‐β‐carbolines by Acid‐Promoted One‐Pot Sequential Formation of C−C and C−N Bonds

“…Aplausible reaction mechanism can be proposed for the formation of tetracyclic tetrahydro-b-carboline derivatives (Scheme 5). Initially,n ucleophilic addition of the b-enaminone 1 to the electrophile 2 take place to give addition product I (Scheme 5), [14b] Entry [a] Acid (equiv) Solvent t [h] [c] Yield [%] [b] 1TFACH 3 pno [c] [a] Reactionc onditions: 1a (0.1 mmol), 2a (0.1 mmol), solvent( 3mL);a ll reactions werei nitially conducteda t7 08Cf or 3h,t hen acid was added at room temperature. [ b] Yields are for isolated products.…”

“…230-232 8C; 1 HNMR (500 MHz, CDCl 3 ): d = 10.61 (br s, 1H), 7.77 (d,J = 8.8 Hz,2H),2H),1H), Crystal data for 3z:C 29 H 30 N 2 O 4 (M = 470.55): monoclinic, space group P2 1 /n (no. 14), a = 14.796(3), b = 7.9123(14), c = 21.764(4) ; b = 98.399(3)8; V = 2520.6(8) 3 ; Z = 4; T = 294.15 K; m(MoKa) = 0.083 mm À1 ; D calc = 1.240 gm À1 m 3 ;2 8207 reflections measured (3.128 2V 56.488), 6084 unique (R int = 0.0231) which were used in all calculations. The final R 1 was 0.0545 [I > 2s(I)] and wR 2 was 0.1477 (all data).…”

“…Te trahydro b-carboline alkaloids are privileged structural motifs widely found in natural products, [1] and are of interesti nm edicinal chemistry [2] and pharmacology. [3] Tryptamine-based polycyclic synthetic molecules have attracted significant attention due to their drug-like properties towards different diseases. [4] Amongt hem, the naturalp roduct harmicine and its analogous have gained considerable attentionf or health care.…”

Ligands of the GABAA Receptor Benzodiazepine Binding Site

“…However, insertion of two atoms between the carbonyl group and the pyridine ring resulted in a marked decrease in the affinity of the compound for the BZ-binding site. Furthermore, this site preferentially recognized the s-cis conformation of the 3-carbonyl group (36). Moreover, in the 3-substituted alkoxy-β-carboline series, the affinity for the BZ-binding site increased as the chain length was increased from methoxy to n-propoxy (37).…”