Cinolazepam

Compound 1c, 5-chloro-2-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-2,3-dihydro-1H-inden-1-one was previously reported from our laboratory showing high affinity binding to the 5-HT₇ receptor (Ki = 0.5 nM). However, compound 1c racemizes readily upon enantiomeric separation. To prevent racemization, we have redesigned and synthesized methyl and carboxyethyl analogs, compounds 2 and 3 respectively, whose binding affinities were similar to those of compound 1c. Compounds 2 and 3 cannot undergo racemization since tautomerism was no longer possible and thus, compound 2 was selected for enantiomeric separation and further evaluation. Upon enantiomeric separation, the levorotatory enantiomer, (-)2 or 2a demonstrated a higher affinity (Ki = 1.2 nM) than the (+)2 or 2b enantiomer (Ki = 93 nM) and a β-arrestin biased functional selectivity for the 5-HT₇ receptor. Although 2a showed about 8 times less activity than 5-HT in the Gs pathway, it showed over 31 times higher activity than 5-HT in the β-arrestin pathway. This constitutes a significant β-arrestin pathway preference and shows 2a to be more potent and more efficacious than the recently published β-arrestin biased 3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine, the N-debenzylated analog of JNJ18038683 (Compound 7).

Benzodiazepines play an omnipresent role in forensic and clin. toxicol. as they are widely used for treatment of sleeping disorders, anxiety disorder, muscle relaxation, seizures, and as drugs of abuse.Apart from these 18 substances, further, benzodiazepines, such as etizolam, phenazepam, tetrazepam, bentazepam, and cinolazepam, have to be taken into consideration when screening for benzodiazepines, as they are offered in various countries worldwide.The aim of the present study was to assess the crossreactivity of 29 designer benzodiazepines as well as of the 2,3-benzodiazepine tofisopam utilizing one CEDIA and one HEIA benzodiazepine assay.There are 18 benzodiazepines marketed in Switzerland, and all of them are controlled by the narcotics law.The results obtained for the 11 compounds which have also been assessed in a previous study by Pettersson Bergstrand et.al are in good agreement for the CEDIA.The CEDIA and the HEIA benzodiazepine kits seem suitable for an initial screening for designer benzodiazepines in urine, as they both show good cross-reactivity for most of the tested compounds