N-3(9)-Arylpropenyl-N-9(3)-propionyl-3,9- diazabicyclo[3.3.1]nonanes as -Opioid Receptor Agonists. Eﬀectson -Aﬃnity of Arylalkenyl Chain Modiﬁcations Ge´rardA.Pinna, a, *GiorgioCignarella, b GiovanniLoriga, a,c GabrieleMurineddu, a,c Jean-MarioMussinu, a StefaniaRuiu, c PaolaFadda d andWalterFratta d a Dipartimento Farmaco Chimico Tossicologico, Universita ` di Sassari, via F. Muroni 23/A, 07100 Sassari, Italy b Istituto di Chimica Farmaceutica e Tossicologica, Universita ` di Milano, viale Abruzzi 42, 20131 Milan, Italy c Neuroscienze S.c.a.r.l., Zona Industriale Macchiareddu, 09010 Uta, Cagliari, Italy d Dipartimento di Neuroscienze, Universita ` di Cagliari, Cittadella Universitaria, 09042 Monserrato, Cagliari, Italy Received29September2001;accepted18December2001 Abstract—Twoseriesof N-3-arylpropenyl-N-9-propionyl-3,9-diazabicyclo[3.3.1]nonanes(1b–j)andofthereverted N-3-propionyl- N-9-arylpropenyl isomers (2b–j) as analogues of the previously reported analgesic N-3(9)-cinnamyl-N-9(3)-propionyl-3,9-diazabi- cyclo[3.3.1]nonanes (DBN) (1a, 2a)weresynthesisedandtheiraﬃnityandselectivitytowardsopioid m-, d-and k-receptors were evaluated.Severalcompounds(1e,i,j–2d,e,f,g,j)exhibiteda m-aﬃnityinthelownanomolarrangewithmoderateornegligibleaﬃnity towards d- and k-receptors. The representative term N-9-(3,3-diphenylprop-2-enyl)-N-3-propionyl-DBN (2d) displayed in vivo (mouse)apotentanalgesiceﬀect(ED 50 3.88mg/kgip)whichfavourablycomparedwiththatofmorphine(ED 50 5mg/kgip).In addition, 2d producedinmicetoleranceafteraperiodtwiceaslongwithmorphine. # 2002ElsevierScienceLtd.Allrightsreserved. Introduction Opioid analgesics are widely used clinically to relieve severepain. 1 The m-opioidreceptorhascommonlybeen suggestedtoberesponsiblefornotonlythetherapeutic eﬀects of opioid analgesic drugs but also for the numeroussideeﬀects.Currently,themajorlimitationin themedicalutilizationofopioidsarisesfromtwopecu- liar problems closely linked to their chronic use: toler- anceanddependence. Clinicians have observed that many patients showed wide-rangingsensitivitytothe m drugs,bothwithregard toanalgesiaandtosideeﬀects. Inthisregard,theﬁndingsobtainedbothinanimalsand clinical studies indicate that genetic factors may inﬂu- ence the variable response of patients to m-opioid analgesics and suggest that these drugs may not act through a single receptor mechanism. Accordingly, the cloning of the m-opioid, MOR1 receptor gene, has demonstratedthepresenceofmultiple m-subtyperecep- tors(splicevariantsdiﬀeringattheintracellularcarboxy terminus)andevidencedthatmorethanone m-receptor isresponsibleforopioidanalgesia. In conclusion, these observations suggest that m-opioid analgesic drugs could bind with diﬀerent aﬃnity to multiple m-opioid receptor sub-types providing an approachforthedevelopmentofnewcompoundsable torelieveacuteandchronicpain,andwhicharelacking ofthetypicalopioidsideeﬀects. 2 Recently, we found that N-3(9)-cinnamyl-N-9(3)-pro- pionyl-3,9-diazabicyclo[3.3.1]nonane (1a, 2a) exhibited a signiﬁcant aﬃnity towards m-opioid receptors with K i =29nMfor 1a and13nMfor 2a. 3 We also found that substitution of the phenyl moiety withCland/orNO 2 groups in various positions mark- edly reduced m-aﬃnity in series 1. Interestingly, in the isomericseries 2,thistrendwasreverted,themajorityof the compounds derived from 2a displaying m-aﬃnity higher(K i 6–8nM)thanthatof 2a. 3 Continuingourinterestinthisarea,thecinnamylchain oftheleadcompounds 1,2a wasmodiﬁedasfollows:(a) insertion at C-3 0 of an additional group such as CH 3 (1,2b),C 6 H 11 (1,2c),C 6 H 5 (1,2d), o,m-Cl–C 6 H 4 (1,2e,f), (b) substitution at the para position of the phenyl groups of the chain with halogen (Cl, F) (1,2h,i)or m-CF 3 (1,2g),and(c)reductionofthedoublebondof 1,2d (1,2j)(Table1). 0968-0896/02/$-seefrontmatter # 2002ElsevierScienceLtd.Allrightsreserved. PII:S0968-0896(01)00436-9 Bioorganic&MedicinalChemistry10(2002)1929–1937 *Correspondingauthor.Tel.:+39-079-228721;fax:+39-079-228720; e-mail:pinger@uniss.it