Stanisław Misztal

A Search for New 5-HT1A/5-HT2A Receptor Ligands. In Vitro and in vivo Studies of 1-[ω-(4-Aryl-1-piperazinyl)alkyl]indolin-2(1H)-ones

A series of 1‐[ω‐(4‐aryl‐1‐piperazinyl)alkyl]indolin‐2(1H)‐one derivatives 2–14 was synthesized in order to obtain ligands with a dual 5‐HT1A/5‐HT2A activity. The majority of those compounds (2–5, 7, 10–13) exhibited a high 5‐HT1A (Ki = 2 – 44 nM) and/or 5‐HT2A affinity (Ki = 51 and 39 for 5 and 7, respectively). Induction of lower lip retraction (LLR) and behavioral syndrome and inhibition of these efects evoked by 8‐hydroxy‐2‐(di‐n‐propyl‐amino)tetralin (8‐OH‐DPAT) were used for determination the agonistic and antagonistic activity, respectively, at 5‐HT1A receptors. The 5‐HT2A antagonistic activity was assessed by the blocking effect on the head twitches induced by (±)‐1‐(2,5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane (DOI) in mice. Two of the tested compounds, 1‐{3‐[4‐(3‐chlorophenyl)‐1‐piperazinyl]propyl}‐6‐fluoroindolin‐2(1H)‐one (5) and 1‐{3‐[4‐(2‐methoxyphenyl)‐1‐piperazinyl]propyl}indolin‐2(1H)‐one (7), demonstrated a high 5‐HT1A/5‐HT2A affinity and an in vivo antagonistic activity towards both receptor subtypes.

Structure and spectral properties of β-carbolines. Part 3. Synthesis and stereochemistry of 1,2,3,4,6,7,9,10,15b,15c-decahydropyrido[1″,2″:1′,2′]pyrazino[4′,3′:1,2]pyrido[3,4-b]indoles

Diastereoisomers of a new heterocyclic system, i.e. 1,2,3,4,6,7,9,10,15b,15c-decahydropyrido-[1″,2″:1′,2′]pyrazino[4′,3′:1,2]pyrido[3,4-b]indoles (7a) and (7b), as well as their 6- and 7-oxo derivatives (5a),(5b) and (2a),(2b), respectively, were synthesized. The structure of individual diastereoisomers was determined using 1H and 13C NMR techniques.

Structure and Spectral Properties of b-Carbolines, Part 6. Regiooooselectivity of Cyclocondensation of Spiro[piperidine-m',1-(1,2,3,4-tetrahydeo-b-carbolines)] with Aldehydes

Cyclocondensation of spiro derivatives of 1,2,3,4-tetrahydro-β-carbolines (1) and (5) with aldehydes was found to be a regioselective process. The structure of individual new ring systems, i.e. N-3,7 (2-4), N-2,7 (6) and N-2,14 (7-9) cyclocondensation products, was determined using 1 H nmr techniques

Structure and spectral properties of β-carbolines. Part 4. Synthesis of the new ring system: 9,10,15,15b-tetrahydroindolo[1′,2′ : 4,3]pyrazino[2,1-a]-carbolin-7(6H)-one

1-Indol-2-yl-1,2,3,4-tetrahydro-β-carboline and its 5-methoxy derivative were synthesized by the Pictet-Spengler reaction between tryptamine or 5-methoxytryptamine and indole-2-carbaldehyde, with a high yield. A step-by-step oxidation of the indolyl carbolines led to formation of the appropriate dihydrocarboline derivatives and two analogues of neoeudistomine, the fully unsaturated carbolines. Condensation of the indolyltetrahydrocarbolines with bromoacetyl chloride yielded the appropriate 2-substituted derivatives, which were cyctized to yield the new ring system compounds 9,10,15,15b-tetrahydroindolo[1′,2′ : 4,3]pyrazino[2,1-a]carbolin-7(6H)-ones, the structures of which were determined by using a high-resolution 1H NMR technique.