Synthesis, Molecular Modeling, and Opioid Receptor Affinity of 9,10-Diazatricyclo[4.2.1.1 2,5 ]decanes and 2,7-Diazatricyclo[4.4.0.0 3,8 ]decanes Structurally Related to 3,8-Diazabicyclo[3.2.1]octanes Paola Vianello, ∇,§ Alberto Albinati, § Gerardo A. Pinna, | Antonio Lavecchia, † Luciana Marinelli, † Pier Andrea Borea, ‡ Stefania Gessi, ‡ Paola Fadda, ⊥ Silvia Tronci, ⊥ and Giorgio Cignarella* ,§ Istituto di Chimica Farmaceutica e Tossicologica, Viale Abruzzi 42, 20131 Milano, Italy, Dipartimento Farmaco Chimico Tossicologico, Via Muroni 23/A, 07100 Sassari, Italy, Dipartimento di Chimica Farmaceutica e Tossicologica, Universita ` di Napoli “Federico II”, Via D. Montesano 49, 80131 Napoli, Italy, Dipartimento di Medicina Clinica e Sperimentale, Via Fossato di Mortara 19, 44100 Ferrara, Italy, and Dipartimento di Neuroscienze, Via Porcell 4, 09100 Cagliari, Italy Received August 2, 1999 Various lines of evidence, including molecular modeling studies, imply that the endoethylenic bridge of 3,8-diazabicyclo[3.2.1]octanes (DBO, 1) plays an essential role in modulating affinity toward μ opioid receptors. This hypothesis, together with the remarkable analgesic properties observed for N 3 propionyl, N 8 arylpropenyl derivatives (2) and of the reverted isomers (3), has prompted us to insert an additional endoethylenic bridge on the piperazine moiety in order to identify derivatives with increased potency toward this receptor class. In the present report, we describe the synthesis of the novel compounds 9,10-diazatricyclo[4.2.1.1 2,5 ]decane (4) and 2,7-diazatricyclo[4.4.0.0 3,8 ]decane (5), as well as the representative derivatives functionalized at the two nitrogen atoms by propionyl and arylpropenyl groups (6a-e, 7a-d). Opioid receptor binding assays revealed that, among the compounds tested, the N-propionyl-N-cinnamyl derivatives 6a and 7a exhibited the highest μ-receptor affinity, and remarkably, compound 7a displayed in vivo (mice) an analgesic potency 6-fold that of morphine. Introduction The nucleus of 3,8-diazabicyclo[3.2.1]octane (see Chart 1, DBO, 1), 1 when substituted on the N 3 and N 8 by propionyl and by an arylalkenyl group (2, 3), has yielded compounds endowed with a central analgesic activity comparable to, or higher than, that of morphine. 2 More recently it was found that the analgesic activity of DBOs is related to their interaction with opioid μ-receptors with affinity in the nanomolar range, similarly to morphine, but with a higher μ/δ selectivity. 3,4 The μ-receptor affinity and analgesic potency of these compounds, as compared with the loss of activity for the corresponding piperazine and equatorial 2,6-dimeth- ylpiperazine derivatives, suggested that the endoethyl- enic bridge of DBO plays an essential role in interacting with the receptor, possibly by fitting into a lipophilic pocket. 5 Indeed, the finding that the μ-affinity of certain 3-arylpropenyl-8-propionyl-DBO derivatives is retained or even improved by reverting the position of the 3,8 substituents suggests that the receptor ligand binding site may in fact possess two such pockets, able to accommodate the endoethylenic bridges of the two series. 5 On the basis of this assumption, we reasoned that a structure bearing two bridges on the piperazine moiety would more efficiently interact with the μ-receptor. Two structures with this requisite are 9,10-diazatricyclo- [4.2.1.1 2,5 ]decane 4, which has the endoethylenic bridges bonded to carbon atoms 1.6 and 2.5, and 2,7-diazatricyclo- [4.4.0.0 3,8 ]decane 5, which has the bridges bonded to carbon atoms 1-8 and 3-6 (see Chart 2). Both com- pounds are so far undescribed in the literature. An appropriate substitution of the nitrogen atoms of 4 and 5 with a propionyl and an arylpropenyl group * To whom correspondence should be addressed. Tel: 39-2-29510843. Fax: 39-2-29514197. E-mail: giorgio.cignarella@unimi.it. § Istituto di Chimica Farmaceutica e Tossicologica. | Dipartimento Farmaco Chimico Tossicologico. † Universita ` di Napoli “Federico II”. ‡ Dipartimento di Medicina Clinica e Sperimentale. ⊥ Dipartimento di Neuroscienze. ∇ Current address: Pharmacia & Upjohn, V.le Pasteur 10, 20014 Nerviano (MI), Italy. Chart 1 2115 J. Med. Chem. 2000, 43, 2115-2123 10.1021/jm991140q CCC: $19.00 © 2000 American Chemical Society Published on Web 05/12/2000