Synthesis and neuropharmacological evaluation of 2-aryl- and alkylapomorphines Attila Sipos, a, * Be ´la Kiss, b E ´ va Schmidt, b Istva ´n Greiner b and Sa ´ndor Bere ´nyi a a Department of Organic Chemistry, University of Debrecen, PO Box 20, H-4010 Debrecen, Hungary b Research Division, Richter Gedeon Ltd, PO Box 27, H-1475 Budapest, Hungary Received 6 September 2007; revised 24 January 2008; accepted 30 January 2008 Available online 5 February 2008 Abstract—A novel synthesis has been elaborated for the pharmacologically remarkable 2-arylapomorphines described and charac- terized in the last few years. This new procedure contains two alternative synthetic routes and has allowed the preparation of several hitherto unknown compounds as well. The pharmacological profile of the previously published and the novel 2-alkyl- and arylapo- morphines has been determined with the application of in vitro and in vivo techniques. For 2-phenyl- (2) and 2-(4-hydroxy- phenyl)apomorphines (3) the superior dopamine agonist profile has been confirmed and for the novel compounds some remarkable results have been observed. Ó 2008 Elsevier Ltd. All rights reserved. 1. Introduction The ability of (R)-apomorphine (1, Fig. 1) and its 2- substituted derivatives for binding to dopamine recep- tors has been widely studied in the last decades. 1 As a result of that, drug products are now commercially available containing apomorphine hydrochloride as ac- tive substance. The indications aimed are those disor- ders which are in connection with the abnormal functioning of dopaminergic system, especially Parkin- son’s disease and erectile dysfunction. It is also known that apomorphine is not dopamine-receptor subtype selective, this feature suggests the need for the prepara- tion of apomorphines modified in 2-position. Several studies into dopamine-receptor binding empha- size the effect of the presence of a hydrophobic group in the proximity of 2-position of the aporphine skele- ton. 2 This effect is in agreement with the model of dopa- mine D 2 receptors suggested by Ramsby et al. According to this model there is a lipophilic cavity on the surface of the receptor next to the binding site. On the basis of this principle, Søndergaard et al. 3 synthesized 2-phenylapomorphine (2) and 2-(4-hydroxy- phenyl)-apomorphine (3) among other 2-arylapomo- phines. These two derivatives have superior affinity to D 2 receptors in comparison to apomorphine (1). Fur- thermore, the D 3 /D 2 selectivity of the above-mentioned derivatives 2 and 3 also exceeded the same ratio for reference compound 1. 2. Chemistry Our conception for the formation of new C–C bond at 2-position was based on Suzuki reaction. 4 Several papers report remarkable effectiveness of palladium catalyzed cross-couplings in the formation of aryl–aryl and aryl–alkyl type C–C bonds starting from aryl halides. 0968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2008.01.057 Keywords: Apomorphine; Dopamine receptor subtypes; D 3 /D 2 selec- tivity; Suzuki–Miyaura reaction. * Corresponding author. Tel.: +36 52512900; fax: +36 52512836; e-mail: asipos@puma.unideb.hu N OH OH R Me H R H Ph OH 1 2 3 1 2 3 4 5 6 6a 7 8 9 10 11 Figure 1. Apomorphine and its 2-aryl derivatives. Available online at www.sciencedirect.com Bioorganic & Medicinal Chemistry 16 (2008) 3773–3779