Imidazo[2,1-b]thiazole System: A Scaffold Endowing Dihydropyridines with Selective Cardiodepressant Activity Roberta Budriesi,* ,† Pierfranco Ioan, † Alessandra Locatelli,* ,† Sandro Cosconati, ‡ Alberto Leoni, † Maria P. Ugenti, † Aldo Andreani, † Rosanna Di Toro, § Andrea Bedini, § Santi Spampinato, § Luciana Marinelli, ‡ Ettore Novellino, ‡ and Alberto Chiarini † Dipartimento di Scienze Farmaceutiche, UniVersità degli Studi di Bologna, Via Belmeloro 6, 40126 Bologna, Italy, Dipartimento di Chimica Farmaceutica e Tossicologica, UniVersità degli Studi di Napoli “Federico II”, Via Montesano 49, 80131 Napoli, Italy, and Dipartimento di Farmacologia, UniVersità degli Studi di Bologna, Via Irnerio 48, 40126 Bologna, Italy ReceiVed June 12, 2007 The synthesis, characterization, and functional in vitro assays in cardiac tissues and smooth muscle (vascular and nonvascular) of a number of 4-imidazo[2,1-b]thiazole-1,4-dihydropyridines are reported. The binding properties for the novel compounds have been investigated and the interaction with the binding site common to other aryl-dihydropyridines has been demonstrated. Interestingly, the novel 4-aryl-dihydropyridines are L-type calcium channel blockers with a peculiar pharmacological behavior. Indeed, the imidazo[2,1-b]thiazole system is found to confer to the dihydropyridine scaffold an inotropic and/or chronotropic cardiovascular activity with a high selectivity toward the nonvascular tissue. Finally, molecular modeling studies were undertaken for the most representative compounds with the aim of describing the binding properties of the new ligands at molecular level and to rationalize the found structure–activity relationship data. Due to the observed pharmacological behavior of our compounds, they might be promising agents for the treatment of specific cardiovascular pathologies such as cardiac hypertrophy and ischemia. Introduction Voltage-gated Ca 2+ channels are heteromultimeric trans- membrane proteins that are made of four or five subunits (R 1 , R 2 , δ, , γ). Among them, the main R 1 subunit allows the selective passage of Ca 2+ ions into excitable cells and controls the voltage sensitivity and the gating mechanism. 1 These proteins have a crucial role in a broad range of cellular processes, such as neurotransmitter release, second messenger cascades, cardiac excitation and contraction, and gene regulation supporting learning and memory. 2 Due to their important functions, voltage-gated Ca 2+ channels have been extensively studied and, to date, different drugs are available that are known to interact with them. Among the others, L-type calcium channel (LTCC a ) blockers have gained a critical role in the treatment of different cardiovascular pathologies. The above-mentioned drugs can be divided in four structurally different classes: 1,4- dihydropyridines (1,4-DHPs), such as Nifedipine, phenylalkyl- amines (PAAs), such as Verapamil, 1,5-benzothiazepines (BTZs), such as (+)-cis-Diltiazem, and pyrrolidineethanamine, such as Bepridil (Chart 1). Each class of LTCC blockers exhibits distinct characteristics in their cardiovascular profiles in mediating antihypertensive, antianginal and antiarrhythmic activities. 3 In particular, Vera- pamil and Diltiazem are essentially nonselective and 1,4-DHPs usually display a vascular selectivity. One obvious reason for the different tissue-selectivity has to be ascribed to the different topographic localization of their binding sites of the channel. It has been demonstrated that these drugs bind at distinct sites within the R 1 subunit of the L-type Ca 2+ channel (Ca V 1) and they noncompetitively affect each other’s binding. 3 Moreover, it can also be argued that the targeted subclass of L-type channel and the state-dependent interactions of LTCC blockers with the protein might have a role in determining tissue selectivity. In addition to the above-described factors, small structural variation on the 1,4-DHPs scaffold led to significant differences in voltage sensitivity of binding, which has a direct influence on the vascular/cardiac selectivity. Interestingly, in our earlier works we demonstrated that compounds such as fluodipine displayed a high cardiac selectivity. 4 The differential tissue-selectivity displayed by LTCC blockers has allowed their employment as “specific probes” for the pharmacological and structural char- acterization of the Ca V 1 channel. 5 To date, several R 1 subunits * To whom corresondence should be addressed. Tel.: +39-051- 2099737(R.B.); +39-051-2099712(A.L.). Fax: +39-051-2099721 (R.B.); +39-051-2099721 (A.L.). E-mail: roberta.budriesi@unibo.it (R.B.); alessandra. locatelli@unibo.it (A.L.). † Dipartimento di Scienze Farmaceutiche, Università degli Studi di Bologna. ‡ Università degli Studi di Napoli “Federico II”. § Dipartimento di Farmacologia, Università degli Studi di Bologna. a Abbreviations: LTCC, L-type calcium channel; 1,4-DHPs, 1,4-dihy- dropyridines; PAAs, phenylalkylamines; BTZs, 1,5-benzothiazepines; GPILSM, guinea-pig ileum longitudinal smooth muscle. Chart 1 J. Med. Chem. XXXX, xxx, 000–000 A 10.1021/jm070681+ CCC: $37.00  XXXX American Chemical Society Published on Web 02/28/2008