Table 1.

Comparison of the features of C2 modifications 3a-f (Chart 1A, Ar = C₆H₅). A check mark indicates favorable (planarity and rigidity, with respect to the binding cleft in the C2-extended adenine region of the A₃AR as in Figure 1) or unfavorable criteria (reactivity) as applied to each linker. All of the maximum lengths shown are within the range of the proposed outward displacement of TM2 in the hybrid A₃AR model.

	Linker	Linker Features
		Planaritya	Rigidityb	Max Lengthc	Potential Reactivityd
a	C≡C	✓	✓	8.00	✓
b	CH2			6.37
c	(CH2)2			5.84
d	cyclopropyl		✓	7.61
e	CH=CH	✓	✓	7.70	✓
f	triazole	✓	✓	8.80

^aAbility to fit in a narrow space. This refers to the planarity of the linker only not of the overall C2 substituent.

^bInability to bend.

^cDistance measured between the C2 of the adenine core and the most distal hydrogen of the phenyl ring.

^dPotential toxicity and/or reactivity with nucleophiles in vivo.